Hemophilia C refers to the deficiency of factor XI which results in bleeding tendencies. Hemophilia C is also known as plasma thromboplastin antecedent (PTA) deficiency or Rosenthal syndrome.
It is a mild form of hemophilia affecting both sexes.
It is predominantly known to occur in Jewish people of Ashkenazi descent.
It is the fourth most common coagulation disorder after von Willebrand’s disease and hemophilia A and B.
The bleeding tendency is usually mild, even in case of severe deficiency as the bleeding risk in hemophilia C is not always influenced by the severity of the deficiency, especially in individuals with partial deficiency.
Therefore, some patients with severe deficiency do not have a bleeding tendency, whereas some patients with mild deficiency bleed excessively.
Hemophilia C equally affects males and females.
People of any age group can be affected.
It must be kept in mind that normal infants younger than age 6 months have low levels of factor XI. After this, factor XI levels do not change with age.
Pathophysiology and Causes
In the intrinsic pathway of the coagulation cascade, factor XIIa activates factor XI and factor IX.
There is another method of activation of factor XI and this direct activation may be more important than the activation due to factor XII.
Patients with severe deficiency of XII are not seen to have a tendency to bleed suggesting that XII controlled activation of XI may not be that important.
Factor XI, on activation, undergoes conversion to a serine protease that leads to activation of factor IX, followed by thrombin generation.
The sustained thrombin generation leads to the activation of thrombin-activatable fibrinolysis inhibitor, which impairs the conversion of plasminogen to plasmin.
Thus being a procoagulant and an antifibrinolytic agent, the lack of factor XI in plasma results in a tendency to bleed.
Alpha-1 antitrypsin is the main inhibitor of factor XIa and is responsible for two-thirds of its inhibition. C1 esterase inhibitor, antithrombin III, and alpha-2 antiplasmin also cause remaining inhibition.
When deficiency of factor XI is severe, bleeding is related to injury, especially when trauma involves tissues rich in fibrinolytic activators, such as the oral mucosa, the nose, and the urinary tract.
Patients of hemophilia C, even with severe factor XI deficiency do not spontaneously bleed. This is in contrast to hemophilia B or A
The severity of the deficiency is based on plasma factor XI clotting activity. Severe factor XI deficiency is present when the activity of factor XI in plasma is less than 1-15 IU/dL.
Genetic mutations are the main causes of hemophilia C.
The inheritance pattern of factor XI is autosomal but not completely recessive, because heterozygotes may have bleeding.
Acquired factor XI deficiency occurs in patients who develop inhibitors to this protein. It is seen mainly in patients with other immunologic diseases like lupus erythematosus.
Noonan syndrome is characterized by congenital cardiac abnormalities, short stature, and mental retardation. Factor XI deficiency is a common finding in Noonan syndrome.
Clinical Presentation of Hemophilia C
Bleeding after surgery or after injury is the usual presenting symptom in individuals with hemophilia C. But preoperative coagulation screening reveals an abnormal aPTT and patients may be diagnosed beforehand.
An abnormal activated partial thromboplastin time (aPTT), especially in presence of the family history suggests a hereditary bleeding disorder.
Patients with systemic lupus erythematosus and other immunologic diseases and Noonan syndrome should be looked for hemophilia C.
Some unusual presentations with spontaneous bleeding have been reported and thought to be aggravated by other pathologies. These unusual presentations include the following:
- Massive hemothorax
- Cerebral hemorrhage
- Subarachnoid hemorrhage
- Spinal epidural hematoma with the Brown-Sequard syndrome
Unlike hemophilia A and B, hematuria and spontaneous hemarthrosis are rare.
Menorrhagia is an important finding, and abnormal bleeding after childbirth may occur in females.
- Hemophilia A and B
- Pediatric Von Willebrand Disease
- Platelet dysfunction
- Other clotting factor deficiencies
- Uncommon coagulopathies
Laboratory studies for suspected hemophilia C should include the following:
- Complete blood count
- Factor XI levels
- Factor VIII and von Willebrand factor levels
- Coagulation profile
- Prothrombin time (PT)
- Thrombin time (TT)
The aPTT is usually prolonged in factor XI deficiency whereas the PT and TT are normal.
Individuals with factor XI levels less than 15-20 U/dL are usually at risk of excessive bleeding after surgery or trauma but it must be remembered that there is a very poor, relationship between factor XI level and bleeding.
Not required for diagnosis but can be done to gauge the extent of bleed.
Genetic analysis for the mutation in factor XI is may help to know the mutation.
Patients with Hemophilia C do not generally bleed spontaneously. So there is no need for prophylaxis.
If recognized early, all vaccinations should be given subcutaneously because of the risk of inducing a muscle hematoma. These patients should be vaccinated against hepatitis A virus and hepatitis B virus because they have or may be exposed to plasma products as part of their treatment.
There are no activity restrictions like hemophilia A or B.
Managing Bleeding in Surgical Procedures
Patients with severe factor XI deficiency usually require replacement therapy before they undergo a surgical procedure, even if they have never bled after surgery before. Antifibrinolytic agents alone may be suitable for some patients.
The use of nonsteroidal anti-inflammatory drugs should be avoided.
Replacement with plasma products must be coordinated with the hemophilia treatment center.
Factor replacement therapy may be needed for 5-7 days after major surgery.
Therapy aims at replacing the deficient factor and in case of bleeding using other measures, such as fibrin glue and antifibrinolytics.
Following options are available for patients with factor XI deficiency
- Fresh-frozen plasma
- Factor XI
- Recombinant activated factor VII in case of
Antifibrinolytics are particularly useful and may be sufficient for dental extractions even in patients with severe deficiency.
- Fibrin glue
- Desmopressin – a synthetic antidiuretic hormone
Replacement therapy during and/or after vaginal delivery is not mandatory in women with severe deficiency. It can be restricted to patients in whom severe hemorrhage occurs.
For women undergoing cesarean delivery, additional precautions are required.
Tooth extractions can be managed by using only antifibrinolytic agents without replacement therapy. Epidural anesthesia without replacement therapy is not recommended in these patients.
- Gomez K, Bolton-Maggs P. Factor XI deficiency. Haemophilia. 2008 Nov. 14(6):1183-9.
- Batty P, Honke A, Bowles L, et al. Ongoing risk of thrombosis with factor XI concentrate: 5 years experience in two centres. Haemophilia. 2015 Jul. 21 (4):490-5.
- Bauduer F, de Raucourt E, Boyer-Neumann C, et al. Factor XI replacement for inherited factor XI deficiency in routine clinical practice: results of the HEMOLEVEN prospective 3-year postmarketing study. Haemophilia. 2015 Jul. 21 (4):481-9.