Recombinant factor XIII A‐subunit in a patient with factor XIII deficiency and recurrent pregnancy loss

Essentials

• Inherited factor XIII deficiency is a very rare bleeding disorder.
• We used recombinant factor XIII‐A in a pregnant patient with factor XIII‐A subunit deficiency.
• The patient had a successful pregnancy outcome with no pregnancy related complications.
• The dose of recombinant factor XIII‐A was minimized by using frequent trough level monitoring.

Summary

Inherited factor XIII deficiency is a very rare bleeding disorder, and is one of the causes of recurrent pregnancy loss. The use of plasma‐derived FXIII to improve pregnancy outcomes has been reported. We report a 26‐year‐old woman with FXIII A‐subunit (FXIII‐A) deficiency who was treated with recombinant FXIII‐A and had a successful pregnancy outcome with no pregnancy‐related complications. Our case illustrates that the dose of recombinant FXIII‐A can be minimized and adjusted on the basis of frequent trough level monitoring.

     

Factor XIII cotreatment with hemostatic agents in hemophilia A increases fibrin α‐chain crosslinking

Essentials

• Factor XIII (FXIII)‐mediated fibrin crosslinking is delayed in hemophilia.
• We determined effects of FXIII cotreatment with hemostatic agents on clot parameters.
• FXIII cotreatment accelerated FXIII activation and crosslinking of fibrin and α₂‐antiplasmin.
• These data provide biochemical rationale for FXIII cotreatment in hemophilia.

Summary

Background

Hemophilia A results from the absence, deficiency or inhibition of factor VIII. Bleeding is treated with hemostatic agents (FVIII, recombinant activated FVII [rFVIIa], anti‐inhibitor coagulation complex [FEIBA], or recombinant porcine FVIII [rpFVIII]). Despite treatment, some patients have prolonged bleeding. FXIII‐A₂B₂ (FXIII) is a protransglutaminase. During clot contraction, thrombin‐activated FXIII (FXIIIa) crosslinks fibrin and α₂‐antiplasmin, which promotes red blood cell retention and increases clot stability and weight. We hypothesized that FXIII cotreatment in hemophilia would accelerate FXIII activation, leading to increased fibrin crosslinking.

Methods

FVIII‐deficient plasma and whole blood were clotted with or without hemostatic agents (FVIII, rFVIIa, FEIBA, or recombinant B‐domain‐deleted porcine FVIII [rpFVIII]) and/or FXIII. The effects on FXIII activation, thrombin generation, fibrin and α₂‐antiplasmin crosslinking, clot formation and clot weight were measured by western blotting, calibrated automated thrombography, thromboelastography, and clot contraction assays.

Results

As compared with FVIII‐treated hemophilic plasma, FVIII + FXIII cotreatment accelerated FXIIIa formation without increasing thrombin generation. As compared with buffer‐treated or FXIII‐treated hemophilic plasma, FVIII treatment and FVIII + FXIII cotreatment increased the generation and amount of crosslinked fibrin, including α‐chain‐rich high molecular weight species and crosslinked α₂‐antiplasmin. In the presence of FVIII inhibitors, as compared with hemostatic treatments (rFVIIa, FEIBA, or rpFVIII) alone, FXIII cotreatment increased whole blood clot weight.

Conclusion

In hemophilia A plasma and whole blood, FXIII cotreatment with hemostatic agents accelerated FXIIIa formation, increased the generation and amount of fibrin α‐chain crosslinked species, accelerated α₂‐antiplasmin crosslinking, and increased clot weight. FXIII cotreatment with hemostatic therapy may augment hemostasis through increased crosslinking of fibrin and α₂‐antiplasmin.