Current therapy for FXIII deficiencies include recombinant FXIII-A2 for patients with A subunit deficiency, plasma derived FXIII concentrate for patients with either subunit A or B deficiencies, and when these are not available either fresh frozen plasma or cryoprecipitate. To decrease the risk of bloodborne pathogens, the plasma derived or recombinant FXIII concentrates are now recommended over blood products. This will also decrease sensitization to plasma proteins that are responsible for the chills, fever, and rash associated with recurrent exposure to plasma and cryoprecipitate.
Currently, only the plasma derived FXIII concentrate is recommended for both prophylaxis and on demand treatment of acute bleeds. The recombinant FXIII-A2 has an FDA indication for prophylaxis alone, although pharmacokinetic studies suggest it would be effective therapy for on demand treatment as well if the patient is subunit A deficient.
The recombinant FXIII-A2 depends on the patient having normal levels of FXIII-B subunit to form the heterotetrametric FXIIIA2B2 for normal half-life in plasma. If the patient is FXIII-B subunit deficient, however, the recombinant FXIII-A2 half-life is markedly reduced to approximately 8 hours rather than the 6-11 days seen in the FXIII-A subunit deficient patient. Therefore, patients considering recombinant FXIII-A2 should either have FXIII levels drawn as part of a PK study to validate a normal survival, or have their A and B subunits measured as part of the diagnostic work up.
In general, prophylactic therapy is recommended for patients with a history of intracranial hemorrhage, recurrent serious bleeding episodes, or FXIII levels less than 5% activity. Historically, treatment for FXIII deficiency initially centered on cryoprecipitate and fresh frozen plasma. As the half- life of endogenous FXIII is long, ranging from 5 to 11 days, prophylactic therapy with fresh frozen plasma in doses of 10 mL per kg could be given every 4–6 weeks to prevent spontaneous bleeding, particularly intracranial hemorrhage. Cryoprecipitate could be administered without hospitalization in doses of 1 bag per 10–20 kg every 3–4 weeks59 with much smaller volumes and shorter infusion times. On-demand therapy for acute or recurrent bleeding would incorporate severity, site of the hemorrhage and bleeding history to determine frequency of subsequent dosing. Although lifesaving, recurrent exposure to blood products resulted in sensitization reactions with infusions, exposure to possible infectious pathogens, and a dependence on the availability and proximity to a medical center.
In 2012, plasma derived, heat-treated and viral inactivated FXIII concentrate became available for all patients in the US. For 13 years, it was made available to all patients for free, while the necessary data were collected for FDA approval. This was life saving for over 80 patients with this very rare orphan bleeding disorder, and the manufacturer (CSL Behring) was recognized by the National Organization for Rare Disorders (NORD) for its commitment to patients with FXIII deficiency.
As with all other hemophilias, it was a much shorter time to the development of a recombinant form of FXIII-A2 subunit (Novo Nordisk; Bagsvaerd, Denmark), which was approved in 2014 for prophylaxis in patients with severe FXIII A subunit deficiency. This human recombinant FXIII-A2 (rFXIII-A2), is a homodimer that binds with the patient’s own endogenous circulating FXIII-B subunits to form the heterotetramer FXIII-A2B2. This product has a half-life of 6–9 days.60 Interestingly, Lovejoy et al.60 clearly showed that the half-life of infused recombinant FXIII-A2 is significantly shorter in patients with FXIII-B deficiency. Results of the phase 1 clinical trial showed that this product was safe and effective as a possible alternative treatment plan for FXIII-deficient patients.60 Recombinant FXIII-A2 was FDA approved for prophylaxis, but has recently been reported to be highly effective for surgical prophylaxis as well.61
Dosage regimens vary widely for either factor concentrate depending on patient response and pharmacokinetics. This variation is not surprising given the heterogeneity of FXIII-deficient patients, the presence or absence of intracellular FXIII subunits or activity modifying polymorphisms. Dosages ranging from 10 to 35 U per kg body weight may be necessary to prevent bleeding for prophylaxis. Because of the long half-life of both the plasma derived and recombinant FXIII, dosing can be administered at 4- to 6-week intervals, but should be based on a PK study for each patient. Treatment with FXIII concentrate resulted in restoration of normal clotting pattern as measured by thromboelastography.62
Surgery and Pregnancy
Decidual bleeding usually begins from 5 to 6 weeks of gestation leading to spontaneous abortion if replacement therapy is not given. Perinatal management should maintain FXIII-A levels at least 2-3%, and ideally greater than 10% to prevent miscarriage.56 Administration of FXIII concentrate at 250 IU every week is sufficient to maintain plasma FXIII-A level greater than 10% in early gestation (less than 22 weeks gestation). Higher dosing at 500 IU weekly is adequate replacement for later in pregnancy. At the time of delivery, a large dose at 1000 IU is recommended to achieve levels greater than 30% to avoid bleeding complications.63
For surgical procedures, FXIII may need to be given more frequently to maintain levels above 10-20% and prevent poor healing. However, there are no prospective, controlled trials to validate ideal levels in these clinical scenarios.
Rare Coagulation Disorders Resource Room, an extension of the RBDD Registry (eu.rbdd.org), was developed in collaboration with the Indiana Hemophilia & Thrombosis Center (www.innovativehematology.org).
The Resource Room serves as a platform to promote international collaboration to increase knowledge of these very rare disorders and to improve the care of affected individuals. The international RBDD mission, under the leadership of Dr. Peyvandi, will continue to be expanded over time.
The Resource Room thanks all contributing authors of the website articles that have made this valuable information available to the global community of both individuals affected with rare coagulation disorders and their healthcare providers.
