These very rare factor deficiencies, from factor XIII deficiency, the rarest, occurring in an estimated 1 out of 5 million people, to factor XI deficiency, occurring in about 1 out of 100,000, were all discovered and identified in the 20th century. The majority of these conditions were only identified within the last 60-70 years. Here you will find information on how factor deficiencies I, II, V, VII, X, XI, XII and XIII are inherited identified and managed.
Factor I (Fibrinogen) Deficiency
Factor I deficiency is a collective term for three rare inherited fibrinogen deficiencies. It was first described in 1920 by two German physicians. Fibrinogen helps platelets stick together to form the initial “plug” after an injury. Fibrinogen deficiencies can be quantitative or qualitative, depending on whether the fibrinogen is deficient or defective. The quantitative disorders are afibrinogenemia,when fibrinogen is absent, and hypofibrinogenemia, when some protein with normal structure is present but below levels needed for normal clotting. Dysfibrinogenemia is a qualitative disorder in which normal amounts of fibrinogen are manufactured by the liver, but they don’t clot properly.
Factor I deficiency is inherited in an autosomal recessive fashion, which means that both parents must carry the gene to pass it on to their children; it affects men and women equally. Afibrinogenemia is very rare, occurring in 1-2 people per million.. Dysfibrinogenemia is inherited in an autosomal dominant manner, which means that only one parent must carry the gene to pass it on to a child. Hypofibrinogenemia can be inherited in either manner.
Afibrinogenemia and hypofibrinogenemia are usually diagnosed in newborns who exhibit excessive bleeding from the umbilical cord and after circumcision. Easy bruising, nose and mouth bleeds, and soft tissue bleeds are common. Joint and muscle bleeds can also occur. Women with afibrinogenemia typically have menorrhagia (long, heavy periods) and difficulties carrying a baby to term because fibrinogen plays a role in embryo implantation. People with dysfibrinogenemia experience prolonged wound healing and are at increased risk of blood clots in the veins.
Tests to diagnose factor I deficiency measure the amount of fibrinogen in the blood and the time it takes for the blood to clot during the prothrombin time (PT) test, activated partial thromboplastin time (aPTT) test and thrombin clotting time (TCT) test.
In 2009, the FDA approved RiaSTAP ™, the first factor concentrate, to treat afibrinogenemia and hypofibrinogenemia in patients with <50 mg/dL of fibrinogen. RiaSTAP can’t be used in patients with dysfibrinogenemia because of the risk of blood clots. For them, fresh frozen plasma or cryoprecipitate is recommended.
Factor II (Prothrombin) Deficiency
Factor II (FII) deficiency, also called prothrombin deficiency, was first identified in 1947 by Dr. Armand Quick. The incidence is estimated at 1 in 2 million in the general population. Factor II deficiency is inherited in an autosomal recessive fashion, meaning that both parents must carry the gene to pass it on to their children; it affects men and women equally.
Prothrombin is a precursor to thrombin, an enzyme that converts fibrinogen into fibrin to strengthen a clot. Dysprothrombinemia results when there is an abnormality in the structure of prothrombin. Hypoprothrombinemia occurs when the body doesn’t produce enough prothrombin. Symptoms include excessive umbilical cord bleeding, easy bruising, frequent nosebleeds and hemorrhaging after surgery or trauma. Women with FII deficiency experience menorrhagia, heavy menstrual bleeding, and postpartum hemorrhage after childbirth. Joint bleeding is uncommon.
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 near or at 50% of normal have little to no bleeding problems. Inherited FII deficiency must be distinguished from the acquired form. Acquired FII deficiency is caused by several factors: long-term use of antibiotics, bile obstruction, impaired absorption of vitamin K from the intestines and severe liver disease. It is more common than the inherited form.
Treatment to control bleeding is achieved using prothrombin complex concentrates (PCCs) or fresh frozen plasma (FFP). PCCs differ in the amount of FII they contain depending on the manufacturer, which complicates treatment. Because PCCs can increase the risk of blood clots, they are typically only prescribed for surgery or after trauma.
Factor V (Labile Factor, Proaccelerin) Deficiency (Owren’s Disease, Parahemophilia)
Factor V (FV) deficiency was first described in a Norwegian patient in 1943 and reported by Dr. Paul Owren in 1947. Its incidence is about 1 in 1 million; fewer than 200 cases have been documented worldwide. It should not be confused with factor V Leiden, a clotting disorder.
The FV protein is a catalyst, accelerating the process by which prothrombin is converted to thrombin, the initial step in clot formation. FV deficiency is usually inherited in an autosomal recessive fashion, meaning both parents must carry the gene to pass it on to their children; it affects men and women equally.
Common characteristics of FV deficiency are bruising, bleeding under the skin, and nose, gum and mouth bleeds. Babies with severe FV deficiency are at increased risk of intracranial hemorrhage, or bleeding in the brain. People with severe FV deficiency can also experience bleeding in the lungs and gastrointestinal tract, which can be life threatening. Women frequently have menorrhagia, long, heavy periods.
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 platelet function may be affected.
Fresh frozen plasma (FFP) is the only treatment available, as no commercially available factor V concentrate exists. In acute cases of severe bleeding, the addition of platelet concentrates may be needed. Solvent-detergent FFP may contain a more reliable level of FV than standard FFP.
Combined FV/FVIII Deficiency
Combined factor VIII (FVIII) and factor V deficiency is a very rare disorder, found in fewer than 100 patients from 60 families worldwide, mostly in Iran, Israel and Italy. Most cases are mild to moderate. Symptoms can include frequent nosebleeds, easy bruising, and excessive bleeding after injury or surgery. Women can experience menorrhagia and postpartum hemorrhage. Treatment includes fresh frozen plasma. In some cases, bleeds may be treated with FVIII concentrates and desmopressin acetate, the synthetic version of the hormone vasopressin.
Factor VII (Labile Factor or Proconvertin) Deficiency (Alexander’s Disease)
Factor VII (FVII), or proconvertin, deficiency was first recognized in 1951. Considered the most common of rare bleeding disorders its incidence is estimated at 1 per 300,000-500,000. It is inherited in an autosomal recessive fashion, meaning both parents must carry the gene to pass it on to their children; it affects men and women equally.
FVII is a protein that, when bound to tissue factor, initiates the clotting cascade, which leads to the formation of a blood clot.
Symptoms are usually linked to the level of FVII in the blood, but not always. For instance, some people with low FVII levels may have mild symptoms.
Babies are often diagnosed with FVII deficiency within the first 6 months of life, after sustaining a bleed in the central nervous system, such as an intracranial hemorrhage, or gastrointestinal tract. People with severe FVII deficiency experience joint and muscle bleeds, easy bruising and bleeds after surgery. Bleeds can also occur in the skin, mouth, nose and genitourinary tract. Women often experience severe menorrhagia, long, heavy periods.
Diagnosis is made through activated partial thromboplastin time (aPTT) test and prothrombin time (PT) test. Diagnosis can be confirmed with a FVII assay. Acquired factor VII deficiency can occur in patients with liver disease and vitamin K deficiency, and in those taking oral anticoagulants.
The main treatment for FVII deficiency is recombinant factor VIIa (rFVIIa). Prothrombin complex concentrates (PCCs) can also be used, but the amount of factor VII they contain can vary considerably. Fresh frozen plasma (FFP) is another option. In some patients, the use of FFP has led to blood clots.
FACTOR X (Stuart-Prower Factor) DEFICIENCY
Factor X (FX), or Stuart-Prower factor, deficiency was first identified in the 1950s in the US and England in two patients: Rufus Stuart and Audrey Prower. The incidence of FX deficiency is estimated at 1 in 500,000 to 1 in a million. Inheritance is autosomal recessive, meaning females and males can equally be affected. The factor X protein plays an important role in activating the enzymes that help to form a clot. It needs vitamin K for synthesis, which is produced by the liver.
People with mild FX deficiency experience easy bruising, nose or mouth bleeds, and bleeding after trauma or surgery. Symptoms for patients with severe FX deficiency include excessive umbilical cord bleeding, joint bleeds, intramuscular bleeds, and a high risk of intracranial hemorrhage in the first weeks of life.
Women with FX deficiency may additionally exhibit menorrhagia, or heavy menstrual bleeding. Pregnant women with FX may experience first trimester miscarriage or post-partum hemorrhage and should receive consultation by a hematologist and obstetrician prior to delivery.
Diagnosis is made through family history, prothrombin time (PT) test, partial thromboplastin time (PTT) or activated partial thromboplastin time (APTT) test. Diagnosis can be confirmed by a FX assay.
In October 2015, the U.S. FDA approved Coagadex®, a coagulation Factor X (Human) product, manufactured by BioProdcuts (BPL). Coagadex®, a plasma derived concentrate, is indicated for individuals (aged 12 and older) with hereditary Factor X deficiency for on-demand treatment and control of bleeding episodes, and for the perioperative management of bleeding in patients with mild hereditary Factor X deficiency.
Prior to this product becoming available, fresh-frozen plasma (FPP) or plasma-derived prothrombin complex concentrates (PCCs) were the only options for treatment of bleeds. However, the amount of FX varies between PCCs (and from lot to lot). Treatment with PCCs should be used cautiously because at higher volumes they can produce blood clots.
Antifibrinolytic agents, such as aminocaproic acid or tranexamic acid, or topical therapies, such as nosebleed powders or fibrin glue, may relieve bleeding symptoms in patients with mild symptoms.
FACTOR XI DEFICIENCY (Hemophilia C, Plasma Thromboplastin Antecedent (PTA) Deficiency, Rosenthal Syndrome)
Factor XI (FXI) deficiency, also called hemophilia C, plasma thromboplastin antecedent deficiency and Rosenthal syndrome, was first recognized in 1953 in patients who experienced severe bleeding after dental extractions. Its incidence is estimated at 1 in 100,000 in the general population. In Israel, FXI deficiency occurs in up to 8% of Ashkenazi Jews because of intermarriage.
Severe FXI deficiency is inherited in an autosomal recessive pattern, meaning both parents must carry the mutated gene in order for their children to be affected. In some cases, FXI deficiency can also be inherited in an autosomal dominant pattern, meaning children with only one affected parent may inherit the condition. However, people with only one copy of the mutated gene rarely exhibit severe symptoms. Men and women are affected by FXI deficiency equally.
FXI plays an important role in the clotting cascade, which leads to a clot. It helps generate more thrombin, a protein that converts fibrinogen to fibrin, which traps platelets and helps hold a clot in place.
FXI levels in the blood do not necessarily correlate with bleeding symptoms. People with low levels may bleed less than those with higher levels. Although some patients experience frequent nosebleeds or soft tissue bleeds, others first experience hemorrhaging only after tooth extraction, such as for wisdom teeth, surgery or trauma. Further, bleeding may be delayed after these procedures. Women may not know they have FXI deficiency until they experience menorrhagia, or heavy menstrual periods, and postpartum bleeding. Joint and muscle bleeds are uncommon.
Diagnosis is made through a bleeding time test, platelet function tests, and prothrombin time (PT) and activated partial thromboplastin time (aPTT) tests. A FXI assay helps confirm the diagnosis.
In the US there are no FXI concentrates available. However, there are two FXI concentrates manufactured in Europe, one by Bioproducts Laboratories (BPL) in the UK, the other by LFB in France, but only for limited patient use.
Fresh frozen plasma (FFP) is normally used for treatment. However, because FXI is not concentrated in FFP, large amounts of it may be needed. This can lead to blood clots, so FFP must be administered carefully.
Fibrin glue works well to maintain clots after mouth bleeds. When combined with FFP, it arrests bleeding after circumcision and hernia repair. Antifibrinolytics, such as aminocaproic acid, help control nosebleeds and bleeding after tooth extraction.
FACTOR XII (Hageman Factor) DEFICIENCY
Factor XII (FXII) deficiency, also called Hageman factor deficiency, was first identified in 1955 in John Hageman. Its incidence is estimated at 1 in a million. FXII deficiency is inherited in an autosomal recessive fashion, meaning both parents must carry the gene to pass it on to their children; it affects men and women equally. It is more common in Asians than other ethnic groups.
FXII interacts with the activation of FXI to FXIa to generate thrombin, a protein that converts fibrinogen to fibrin, which traps platelets and helps hold a clot in place.
Some people with FXII deficiency experience poor wound healing. However, most do not display bleeding manifestations, even after major surgery.
Since bleeding time is usually normal, diagnosis is made by a prolonged activated partial thromboplastin time (aPTT) test. A factor XII assay helps confirm the diagnosis.
No treatment is required.
FACTOR XIII (Fibrin Stabilizing Factor) DEFICIENCY
Factor XIII (FXIII), or fibrin stabilizing factor, deficiency was first reported in the literature in 1960. It is the rarest factor deficiency, occurring in 1 per 5 million births. It is inherited in an autosomal recessive fashion, meaning that both parents must carry the gene to pass it on to their children; it affects men and women equally.
FXIII protein stabilizes the formation of a blood clot. Without it, a clot will still develop, but will then break down and cause recurrent bleeds. Umbilical cord bleeding is common in factor XIII deficiency, reported in almost 80% of cases. Up to 30% of patients sustain a spontaneous intracranial hemorrhage, a brain bleed, which is the leading cause of mortality. Other symptoms of FXIII deficiency include bruising, nose and mouth bleeds, muscle bleeds and delayed bleeding after surgery.
Women can experience menorrhagia, long, heavy menstrual periods, and repeat miscarriages. Men with FXIII deficiency may show signs of infertility.
Because patients with FXIII deficiency form a clot, clotting tests come back normal. Instead, diagnosis is made using FXIII assays and a clot solubility test.
In February 2011, the US Food and Drug Administration (FDA) approved Corifact®, a product manufactured by CSL Behring to prevent bleeding in people with congenital FXIII deficiency. In 2013, the FDA expanded the use to include peri-operative management of surgical bleeding in adults and children. Corifact is given via intravenous infusion.
Corifact is made from the pooled plasma of healthy donors. It can be used for patients lacking FXIII or who have reduced levels of it. People receiving Corifact may develop antibodies against FXIII, making the product ineffective. If higher than recommended doses are given, there is a risk of clot formation.
In December 2013, the FDA approved Tretten®, manufactured by Novo Nordisk, for routine prophylaxis in people with congenital FXIII A-subunit deficiency. It is an intravenous infusion product for children and adults; 95% of patients with FXIII deficiency have the A-subunit deficiency. Tretten is the only recombinant product approved to treat these patients. Common side effects include headache, and pain in the extremities and at the injection site.
Cryoprecipitate should not be used to treat patients with FXIII deficiency except in life- and limb-threatening emergencies when FXIII concentrate is not available.