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 V Deficiency
(Also known as Owren’s disease, labile factor deficiency, proaccelerin deficiency or parahemophilia. Not to be confused with Factor V Leiden, which is a type of thrombophilia.)

The deficiency was first described in a Norwegian patient in 1944. The incidence of Factor V deficiency is estimated at 1 per 1 million. It is usually inherited in an autosomal recessive fashion, which means it affects men and women equally. There are some case reports of a dominant pattern of inheritance in some families.

The role of the factor V protein is to be a catalyst or “accelerator” in the process by which prothrombin is converted to thrombin. Common characteristics of factor V deficiency are bruising, nose and mouth bleeds. Severe deep tissue bleeds are uncommon. Among people with severe forms of factor V deficiency, there can be joint bleeding and risks of head bleeds in newborns. Women can also present with menorrhagia.

Diagnosis is made through activated partial thromboplastin time (aPTT) test, prothrombin time (PT) test and thrombin clotting time (TCT) test. Diagnosis can be confirmed with a factor V assay. Factor V is found in both plasma and platelets, so platelets function may also be affected. A very rare condition, known as combined factor VIII and Factor V is characterized by more severe bleeding episodes. The combined FVIII+FV deficiency is a separate disorder that can be mistaken for either mild factor V or mild factor VIII deficiency.

Treatment

There are no available factor V concentrates. Fresh frozen plasma (FFP) is the only treatment available. In acute cases of severe bleeding, the addition of platelet concentrates may be helpful. Depending upon availability, solvent-detergent FFP may contain a more reliable level of Factor V than standard FFP.


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