FXIII Deficiency

Clinical Manifestation

FXIII deficiency is associated with severe bleeding, spontaneous intracranial hemorrhages, poor wound healing and spontaneous abortions. Patients with severe congenital FXIII deficiency usually present with plasma FXIII levels less than 1% and severe bleeding diatheses. Heterozygote patients can have reduced levels of FXIII-A and FXIII-B and will usually be clinically asymptomatic. Our understanding of the heterogeneous nature of factor XIII deficiencies and their clinical course derives primarily through the excellent database and registries established in Europe and internationally over the last decade.52,53

The classification used to correlate factor activity with disease severity in hemophilia A or B — namely, severe, moderate or mild disease — cannot easily be applied to FXIII deficiency because the assays used thus far cannot accurately measure FXIII levels less than 2% activity. Until a more sensitive assay becomes widely available to measure activity, it will be difficult to determine the levels that place patients at greatest risk for bleeding. Certainly, an abnormal clot solubility that indicates a level of less than or equal to 1% has been shown to correlate with the characteristic umbilical bleeding seen after birth and has a high risk of intracranial hemorrhage in the first decade of life.

Acquired FXIII deficiency is much more common. In this setting, deficiency in the enzyme is caused by an inhibitor, usually an autoantibody binding to plasma FXIII and interfering with normal function. Acquired FXIII deficiencies can be associated with severe bleeding complications because of inhibitors directed against FXIII, or they can present with mild bleeding symptoms in association with an underlying condition.8 Inhibitors can develop in association with medications such as isoniazid, penicillin and phenytoin.54

Early manifestations of the disease can occur in the neonatal period with umbilical bleeding presenting a few days after birth.  Umbilical bleeding is a characteristic and frequent finding occurring in 80% of cases.8 The incidence of intracranial hemorrhage has been reported to be 25-30%, a much higher frequency than that reported in hemophilia A or B, and is also the main cause of death or disability in patients with congenital FXIII deficiency. In FXIII-deficient patients, clots may form but are weaker in strength and lack the incorporation of anti-fibrinolytic enzymes such as alpha-1-antitrypsin. The clots are lacking in strength and also begin to breakdown earlier, because of weak cross-linking of fibrin, leading to subsequent episodes of re-bleeding at sites of surgery or trauma. Ecchymosis, intramuscular bleeding, postoperative hemorrhage and mucosal bleeding after dental extraction frequently occur.

Delayed wound healing and recurrent spontaneous miscarriages are all common symptoms of severe FXIII deficiency. In addition to its function in hemostasis, FXIII has a role in angiogenesis, a process affecting wound healing and tissue repair.55 FXIII deficiency not only causes increased uterine bleeding during pregnancy, but also leads to poor formation of the cytotrophoblastic shell, increasing risk for placental detachment and eventual miscarriage within the first trimester.56 Recommendations for factor infusions during pregnancy are significantly different from dosing regimens for prophylaxis or surgery (see Treatment section), but aggressive management can result in successful delivery of a full-term infant.

Acquired FXIII deficiency occurs spontaneously when a patient produces an autoantibody specific for FXIII, resulting in rapid clearance and subsequent bleeding. These autoantibodies to FXIII are usually associated with systemic lupus erythematosus, leukemia, severe liver disease, disseminated intravascular coagulation and inflammatory bowel disease.54 Acquired FXIII deficiency occurs more frequently in middle-aged or elderly individuals who present with spontaneous or post-traumatic deep hematomas. Treatment may include anti-CD20 (rituximab), steroids, cyclophosphamide, IVIG or even plasmapheresis, generally with good response and resolution of the inhibitor within 3-6 months.