Bleeding Disorders

A bleeding disorder is a hereditary disorder in which the clotting ability of the blood is impaired and excessive bleeding results.

Hemophilia

Hemophilia A

A deficiency of clotting Factor VIII (factor 8) is classified as Hemophilia A.

It is a hereditary disorder in which the clotting ability of the blood is impaired and excessive bleeding results. Uncontrolled internal bleeding can result in pain, swelling, and permanent damage, especially to joints and muscles.Hemophilia A is caused by an inherited sex-linked recessive trait with the defective gene located on the X chromosome. Females are carriers of this trait. Fifty percent of the male offspring of female carriers have the disease and 50% of their female offspring are carriers. All female children of a male with hemophilia are carriers of the trait, and are called obligate carriers. One third of all cases of hemophilia A occur when there is no family history of the disorder. Called a spontaneous mutation, these cases of hemophilia develop as the result of a new or spontaneous gene mutation. Genetic counseling may be advised for carriers. Female carriers can be identified by a testing procedure called DNA Carrier Testing. The only way a female could have hemophilia is if her father has it and her mother carries the gene, or if she developed Aquired Hemophilia which is very rare. Women who are carriers can also be asymptomatic carriers, whereby they do experience factor deficiencies.

Severity of symptoms can vary, and severe forms usually become apparent early in life. Prolonged bleeding is the hallmark of hemophilia A and typically occurs when an infant is circumcised as hemophilia occurs primarily in boys. Additional bleeding manifestations make their appearance when the infant becomes mobile.

Mild cases may go unnoticed until later in life when there is excessive bleeding and clotting problems in response to dental procedures, surgery or trauma.

Generally, the first bleeding episode occurs before 18 months of age, often after a minor injury. A child who has hemophilia bruises easily. Even an injection into a muscle can cause bleeding that results in a large bruise (hematoma). Recurring bleeding into the joints and muscles can ultimately lead to crippling deformities.

Internal bleeding may occur anywhere in the body. Bleeding into joints, however, is most common. The incidence of hemophilia A is 1 out of 10,000 live male births. About 17,000 Americans have hemophilia. Women may have it, but it’s very rare. There is no cure for hemophilia. With proper treatment and specialized management, the outcome is good. Most men with hemophilia are able to lead successful and relatively normal lives.

Bleeding episodes can also be life threatening when it occurs in sensitive areas. Bleeding can swell the base of the tongue until it blocks the airway, making breathing difficult. A slight bump on the head can trigger substantial bleeding in the skull, causing brain damage and death. A doctor may suspect hemophilia in a child whose bleeding is unusual. A laboratory analysis of blood samples can determine whether the child’s clotting is abnormally slow. If it is, the doctor can confirm the diagnosis of hemophilia A and can determine the severity by testing the activity of factor VIII.

Hemophilia B

Hemophilia B (also called “Christmas disease”) is a deficiency in clotting factor IX.

Hemophilia A is 7 times more common than Hemophilia B. The incidence of Hemophilia B is 1 out of 34,500 men. The outcome is good with proper treatment and specialized management. Most people with Hemophilia B are able to lead successful and relatively normal lives.

Hemophilia Treatment

Both Hemophilia A and B are treated by infusing a factor product that replaces the patient’s missing clotting factor. The amount infused depends upon the severity of the bleeding episode, the site of the bleed, and the weight of the patient. Factor products are intended for home use and can be self-administered (self-infused), either on a regular basis to prevent bleeding or at the first sign of bleeding. Prophylaxis is the treatment method most commonly used. It involves infusing factor product on a regular schedule in order to prevent bleeding episodes from occurring. By treating before a bleed occurs, factor levels in the blood are more normalized which helps to prevent bleeding episodes and the pain and damage they cause. Both the dose and frequency of factor replacement depend on the severity of the bleeding problem. The dose is adjusted according to the results of periodic blood tests. During a bleeding episode, higher doses of factor product are often needed.

To prevent a bleeding crisis, people with hemophilia and their families can learn to administer factor products at home, and in advance of a heavy period of physical activity, or at the first signs of bleeding.

Centers of excellence for the treatment of bleeding disorders exist throughout the country. The Centers for Disease Control have established that people who do not seek treatment have an 80% greater chance of morbidity and mortality than those patients who do. It is recommended that each hemophilia patient receive an annual checkup, called an annual comprehensive evaluation. At this visit, patients are seen by a physician, a physical therapist, a nurse, a social worker, and others who are integral to bleeding disorder care in a one-stop visit. By bringing together multiple disciplines in one visit, patients are evaluated on many levels. The medical staff then meet to make treatment recommendations in a coordinated effort to enhance the patient’s treatment and quality of life.

vWD

von Willebrand Disease (wWD)

Like hemophilia, von Willebrand Disease (vWD) is a hereditary deficiency or abnormality of clotting factor in the blood. In this case, it is the von Willebrand factor which is a protein that affects platelet function. It’s the most common hereditary disorder of platelet function, affecting both women and men. The disease is estimated to occur in 1% to 2% of the population. The disease was first described by Erik von Willebrand, a Finnish physician, who reported a new type of bleeding disorder among island people in Sweden and Finland. In von Willebrand disease, blood platelets don’t stick to holes in blood vessel walls. Platelets are tiny particles in the blood that clump together at the site of an injury to prepare for the formation of a blood clot. von Willebrand factor causes them to bind to areas of a blood vessel that are damaged. If there is too little von Willebrand factor, or the factor is defective, platelets do not gather properly when a blood vessel is injured. von Willebrand factor is found in plasma, platelets, and blood vessel walls. When the factor is missing or defective, the first step in plugging a blood vessel injury (platelets adhere to the vessel wall at the site of the injury) doesn’t take place. As a result, bleeding doesn’t stop as quickly as it should, although it usually stops eventually. There are no racial or ethnic associations with the disorder. A family history of a bleeding disorder is the primary risk factor.

Researchers have identified many variations of the disease, but most fall into the following classifications:

Type I: Most common and mildest form of von Willebrand disease. Levels of von Willebrand factor are lower than normal. Levels of factor VIII may also be reduced.
Type II: In these people, the von Willebrand factor itself has an abnormality. Depending on the abnormality, they may be classified as having Type IIa or Type IIb. In Type IIa, the level of von Willebrand factor is reduced as is the ability of platelets to clump together. In Type IIb, although the factor itself is defective, the ability of platelets to clump together is actually increased.
Type III: Severe von Willebrand disease. These people may have a total absence of von Willebrand factor and factor VIII levels are often less than 10%.Pseudo (or platelet-type) von Willebrand disease: This disorder resembles Type IIb von Willebrand disease, but the defects appears to be in the platelets, rather than the von Willebrand factor.

Once in a while, people develop what appears to be von Willebrand disease later in life. When this occurs in those who have no family history of the disease, it is thought that they’re probably producing antibodies that destroy or decrease the amount of von Willebrand factor. Some other people have “acquired” a form of the disease in association with another disorder, such as rheumatoid arthritis, systemic lupus erythematosus, kidney disease and certain cancers

The life span of patients is usually normal length. Since the disease is genetically transmitted, genetic counseling may be recommended for parents. von Willebrand disease can be more complicated for women because of obstetric and gynecological issues.

Inheritance Pattern (vWD)

Like hemophilia, the disease is passed down through the genes. But unlike hemophilia, which usually affects only males, von Willebrand disease occurs in males and females equally. A man or woman with the disease has a 50% chance of passing the gene on to his or her child. Types I and II are usually inherited in what is known as a “dominant” pattern. This means that if even one parent has the gene and passes it onto a child, the child gets the disease. Whether the child has no symptoms, mild symptoms, or, less commonly, severe symptoms, he or she definitely has the disease. Regardless of severity of the symptoms, the child can still pass the gene on to his or her own offspring. Type III von Willebrand disease, however, is usually inherited in a “recessive” pattern. This type occurs when the child inherits the gene from both parents. Even if both parents have mild or asymptomatic disease, their children are likely to be severely affected. These patterns of inheritance differ from hemophilia, which is caused by a defect in one of the “sex linked” chromosomes. A man with hemophilia cannot pass the gene on to a son, because the abnormality is carried on the X chromosome, and a man contributes only a Y chromosome to his male offspring. von Willebrand disease is found on the autosomal chromosomes and therefore can be inherited by either males or females. von Willebrand disease can often be traced through several generations in a family. Some have symptoms while others just carry the gene.

Rare Bleeding Disorders

Other Factor Deficiencies

There are ten clotting factors that are necessary in forming a blood clot. Deficiencies in factors VIII and IX are well known to most people, but what of the other factor deficiencies? Not everyone is as familiar with these conditions because they are diagnosed so rarely. To date, deficiencies in eight of the lesser-known coagulation factors have been documented in the medical literature. Many of these disorders were only discovered or described within the last 40 years.
In most cases, rare factor deficiencies are not genetically sex-linked. They occur in equal frequency among men and women. By and large the gene is passed down in an autosomal recessive fashion. This means that when the factor deficiency is inherited from only one parent, the child will be a carrier of the condition, but usually not have symptoms. It is possible for people to inherit a gene from both parents, but this happens very rarely and usually means a more severe manifestation of the disease.
Obtaining a detailed family history is an important component to diagnosing the condition. Most people with rare factor deficiencies are best seen by hematologists at hemophilia treatment centers. Making a proper diagnosis for some of these rare conditions requires a quality lab and an experienced hematologist. To find a treatment center located closest to you, click here.
Not all factor deficiencies have the same severity. Not everyone with these disorders needs treatment. However for those who do, the treatments available for people with rare factor deficiencies are not optimal. Many people in the United States with rare factor deficiencies need to take fresh frozen plasma, prothrombin complex concentrates (PCCs) or cryoprecipitate.
Since there are such a small number of patients with these conditions, there are few clinical studies regarding the use of products to treat them. Without solid clinical data, obtaining FDA approval for products is extremely difficult. Very few pharmaceutical companies will choose to invest the research dollars needed to produce such products for so few patients.

Factor I Deficiency

(Also known as Fibrinogen deficiency, afibrinogenemia, dysfibrinogenemia or hypofibrinogenemia)

Factor I deficiency is actually a collective term for several rare inherited fibrinogen deficiencies. Fibrinogen may be absent from the blood altogether (afibrinogenemia), present in only very low levels in the blood (hypofibrinogenemia), or measurable in normal quantities but defective (dysfibrinogenemia).
The incidence of Factor I deficiency is estimated at 1 to 2 per million. It is inherited in an autosomal recessive fashion, which means it affects men and women equally.
Fibrinogen helps platelets to glue together to form the initial “plug” in response to an injury. Therefore, people with factor I deficiency, have a combined bleeding disorder because both platelets and clotting are abnormal. The severity of the disorder is directly related to the amount of fibrinogen present.
Afibrinogenemia and hypofibrogenemia are usually diagnosed in newborns who can present with head bleeds, bleeding after circumcision and from the site of the umbilical cord. Easy bruising, nose and mouth bleeds, and soft tissue bleeds are also common. Joint bleeding is relatively uncommon. Women with afibinogenemia have an increased risk of spontaneous abortion. Persons with dysfibrinogenemia may have a disposition to thrombosis.
Diagnosis is made by measuring the amount of fibrinogen in the blood, prothrombin time (PT) test, activated partial thromboplastin time (aPTT) test, and thrombin clotting time (TCT) test.

Treatment

For now, cryoprecipitate is the treatment of choice in the United States. FFP may be given, but cryoprecipitate is used more often to avoid volume overload. There are no Factor I concentrates available for use in the U.S. However, there are three fibrinogen concentrates being used in Europe and Japan. There have also been some reports of adverse reactions with use of these concentrates.

Factor II Deficiency

(Also known as prothrombin deficiency)
Factor II deficiency is quite rare, with only 26 cases reported in the medical literature. The incidence is estimated at 1 in 2 million. It is inherited in an autosomal recessive fashion, which means it affects men and women equally.

Prothrombin is a precursor to thrombin, which converts fibrinogen into fibrin which in turn strengthens a protective clot. Factor II deficiency usually takes the form of an abnormality in the structure of prothrombin rather than a lack of the protein itself. People with a more severe factor II deficiency have severe bruising, bleeding from the nose and mouth, menorrhagia, as well as muscle bleeds, head bleeds and bleeding after trauma. Joint bleeding is rare.

Diagnosis is made with a prothrombin time (PT) test and an activated partial thromboplastin time (aPTT) test. Levels of prothrombin deficiency can range from 2% to 50% of normal. Patients with levels reaching 50% of normal have little to no bleeding problems. The inherited condition must be distinguished from the acquired form of Factor II, which is also associated with bleeding. Hereditary Factor II deficiency has also been reported as part of a combined disorder with factor VII, IX, X and protein C and S.

Treatment

Moderate bleeding can be treated with Fresh Frozen Plasma. Correction of prothrombin can also be achieved with the use of Prothrombin complex concentrates (PCCs). However, there are differences in the amount of factor II present in PCCs, depending upon the product. There are reported risks of thromboembolic complications with certain use of PCCs.

Factor VII Deficiency

(Also known as Alexander’s disease, stable factor deficiency, or proconvertin deficiency. Not to be confused with acquired factor VII deficiency, which is associated with liver disease.)

Factor VII was first recognized in 1951, and originally named serum prothrombin version accerlerator (SPCA) deficiency. Although the published incidence of Factor VII deficiency is estimated at 1 in 500,000, the disorder may be more common. It is inherited in an autosomal recessive fashion, which means it affects men and women equally.

The factor VII protein is part of the cascade of clotting factors that form the chain leading to a protective blood clot. Factor VII deficiency is usually severe. In fact patients with less than 1% Factor VII activity experience similar symptoms to hemophilia. People with severe factor VII are prone to joint bleeds. In addition to spontaneous nosebleeds, people can experience bleeds in the stomach, intestines and urinary tract. Head bleeds and muscle bleeds have also been reported. Women can have severe menorrhagia.

Diagnosis is made through activated partial thromboplastin time (aPTT) test, prothrombin time (PT) test and thrombin time (TT) test. Diagnosis can be confirmed with a factor VII assay. There have been instances of combined Factor VII deficiencies with cases of Factors II, IX and X.

Treatment

In July 2005, Novo Nordisk received FDA-approval for a new usage indication of its recombinant factor VIIa product Novoseven® to treat bleeding episodes in patients with factor VII deficiency. Prothrombin complex concentrates (PCCs) can also be used to treat Factor VII deficiency. However, the amount of factor VII contained in these products vary considerably among PCCs. Not only is there a marked difference in factor content between the different commercial preparations, but factor content can also vary between product lots produced by the same manufacturer.

Patients with factor VII deficiency can also be treated with fresh frozen plasma (FFP). However, volume constraints may limit the amount of FFP that can be used. There have been cases of thrombosis reported in people with factor VII deficiency.

Factor X Deficiency

(Also known as Stuart-Prower Factor Deficiency.)
Factor X deficiency was first discovered in a man with the surname Stuart from North Carolina. While his doctors had originally thought he might have factor VII deficiency, a woman with the surname Prower was determined to have the same clotting abnormality. Researchers realized that this was a new factor and called it the Stuart-Prower factor. It was later renamed Factor X deficiency.

The incidence of Factor X is estimated at 1 in 500,000 births. It is inherited in an autosomal recessive fashion, which means it affects men and women equally.

The factor X protein activates the enzymes that help to form a clot. Several genetic variations of Factor X with varying degrees of severity have been described in the medical literature. People with mild forms of the deficiency, usually do not experience bleeding episodes, but do have bleeding after trauma or surgery. Patients with severe forms of the disease, commonly have joint bleeding, gastrointestinal bleeds, and hematomas. Spontaneous head bleeds, spinal cord bleeds and bleeding at the site of the umbilical cord have also been reported. Women with Factor X deficiency may have menorrhagia or be susceptible to first trimester miscarriage.

Diagnosis is made through a bleeding time test, prothrombin time (PT) test, and partial thromboplastin time (PTT) test. Diagnosis can be confirmed by a factor X assay, or a ruffle viper venom time assay.

Treatment

There are no factor X concentrates available and fresh-frozen plasma is normally used as treatment. Prothrombin Complex concentrates (PCCs) have been used in patients, but it is important to know that the amount of factor X in each product in not consistent. There has also been a reported risk of thromboembolic complications with PCC product usage.

Factor XI Deficiency

(Also known as Hemophilia C, Plasma Thromboplastin Antecedent (PTA) Deficiency, Rosenthal Syndrome.)

Factor XI was only first recognized in 1953. The incidence of Factor XI is estimated at 1 in 100,000. It is inherited in an autosomal dominant fashion, which means it affects men and women equally. It can occur with greater frequency in people of Ashkenazi Jewish descent because intermarriage among this group has been more prevalent. In Israel, factor XI deficiency has been estimated to be around 8% among Ashkenazi Jews, making it one of the most common genetic disorders in this group.

Factor XI is another part of the cascade of clotting factors that form the chain leading to a protective clot. Some people with Factor XI deficiency may have milder symptoms that those of hemophilia, but there can be quite a bit of variability with this deficiency. Individuals are not likely to bleed spontaneously, and hemorrhage normally occurs after trauma or surgery. Certain procedures carry an increased risk of bleeding such as, dental extractions, tonsillectomies, surgery in the urinary and genital tracts and nasal surgery. Joint bleeds are uncommon. Patients are more prone to bruising, nosebleeds, or blood in the urine. Woman may experience menorrhagia and prolonged bleeding after childbirth.

Diagnosis is made through bleeding time test, platelet function tests and prothrombin time (PT) and activated partial thromboplastin time (aPTT) tests. A specific Factor XI assay is extremely useful in ruling out combined deficiencies.

Treatment

In the United States, there are no factor XI concentrates available and fresh-frozen plasma is normally used for treatment. Since Factor XI is not concentrated in fresh frozen plasma, considerable amounts of plasma may be required to maintain the factor level. In the case of mouth bleeds, antifibrinolytic products such as Amicar can be helpful. Currently there are two factor XI concentrates produced in Europe. One is manufactured through Bioproducts Laboratories (BPL) in the UK. The other product is produced in France through LFB and only for limited patient use.

Factor XII Deficiency

(Also known as Hageman factor deficiency.)
This somewhat mysterious deficiency was first discovered in 1955 and named after John Hageman, the first patient diagnosed with the condition. The incidence of Factor XII deficiency is estimated at 1 in 1 million. This deficiency is inherited in an autosomal recessive fashion, which means it affects men and women equally. It has been reported that factor XII levels seem to be lower among Asians, than any other ethnic group.

The mystery of Factor XII centers on how the protein is a step in the process of forming a clot, but people with the deficiency usually do not experience bleeds and normally do not require treatment. Having a low factor XII level has little to no clinical significance.

Even with major surgery, bleeding manifestations are extremely rare. In fact, most people only get diagnosed by chance, or during pre-screening blood tests for surgery. Since bleeding time is usually normal, diagnosis is made by a prolonged activated partial thromboplastin time (aPTT) test. A specific factor XII assay is necessary to confirm the initial diagnosis.

Treatment

Treatment is usually unnecessary. There is some indication that Factor XII deficiency may predispose people to thrombosis, but this has not been clearly established.

Factor XIII Deficiency

(Also known as Fibrin Stabilizing Factor deficiency.)

This condition is perhaps the rarest of all factor deficiencies. The incidence of Factor XIII deficiency is estimated at one in five million births. It is inherited in an autosomal recessive fashion, which means it affects men and women equally. No racial or ethnic group is disproportionately affected.

Factor XIII is the protein responsible for stabilizing the formation of a blood clot. In the absence of Factor XIII, a clot will still develop but it will remain unstable. When someone has a deficiency of Factor XIII, the tenuously formed clot will eventually break down and cause recurrent bleeds. The prolonged bleeding that is associated with Factor XIII is usually associated with trauma. Among severe patients there is a high risk of head bleeds with or without trauma. Bleeding immediately after surgery is usually not excessive, but can be delayed. Women who go untreated risk spontaneous abortion. Men with the deficiency may show signs of infertility. Common characteristics include soft tissue bleeds, menorrhagia, joint bleeding, and persistent bleeding during circumsicion or at the site of the umbilical cord.

Diagnosis is made by normal coagulation screening tests and a detailed family history. Specific factor XIII assays can confirm the diagnosis. The condition can also be defined by a clot solubility test.

Treatment

There are currently two commercially-produced factor XIII concentrates produced in Europe. One is manufactured by Bio Products Laboratory (BPL) and is only available in the United Kingdom. The other product is called Fibrogammin-P, produced by Beringwerke of Germany. It is only available under IND or through clinical trial in the United States. Neither of these products is FDA approved for use in the United States. For the time being, cryoprecipitate or fresh-frozen plasma is used to treat factor XIII deficiency.

Source: National Hemophilia Foundation, www.hemophilia.org.

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