The most common clinical symptom, seen in over 80% of cases, is bleeding from umbilical stump after birth. Bleeding episodes are usually lifelong and include severe bruising, hematomas, and prolonged bleeding after trauma. Characteristically, bleeding is delayed for several hours or days after trauma. Haemorrhage into the brain or spinal cord area is more common than in other inherited coagulation disorders and can be life-threatening. Plasma replacement is given to pregnant women to prevent spontaneous abortions.

Deficiency of Factor XIII can be corrected with infusions of fresh frozen plasma or factor XIII concentrates. Because of the high incidence of intracranial bleeding and spontaneous abortions, prophylaxis is often recommended.