Correspondence
Factor XIII in the Treatment of Hemophilia A
N Engl J Med 2012; 366:281-283January 19, 2012DOI: 10.1056/NEJMc1113270
- Article
To the Editor:
Patients with hemophilia A (a deficiency of factor VIII [FVIII]) have spontaneous bleeding because of abnormal thrombin generation, which results in the formation of weak, unstable clots.1 The formation of these weak clots is also the result of delayed and reduced activation of coagulation factor XIII (FXIII).2 The standard treatment is based on FVIII substitution to control and prevent bleeding, but this process is expensive and time-consuming. We hypothesized that supraphysiologic levels of FXIII would normalize clot stability at low levels of FVIII.
Clot stability was recorded by means of the changes in plasma turbidity after the simultaneous addition of tissue factor (dilution, 1:40,000) and tissue plasminogen activator (0.75 nM). FVIII-deficient, platelet-poor plasma, spiked with increasing concentrations of recombinant FVIII plus plasma-derived FXIII or buffer, was compared with normal control plasma. The primary end point was the area under the curve (AUC) for turbidity.
The addition of FVIII improved the AUC (Mann–Whitney test, P<0.005), but the maximum concentration (1 IU per milliliter, 100% of normal levels) failed to normalize clot stability (Figure 1AFigure 1
Clot Stability and Thrombin Generation with Increasing Concentrations of Factors VIII and XIII.Panel A shows changes in the area under the curve (AUC) for turbidity after activation with tissue factor and Ca2+ and lysis with tissue plasminogen activator as a means of assessing clot stability. The data show that there is a response to increasing concentrations of factor VIII (FVIII), alone and in combination with factor XIII (FXIII). Panel B illustrates the effect of increasing concentrations of FVIII alone and in combination with varying concentrations of FXIII on thrombin generation (lag time). Panel C shows the effect of increasing concentrations of FVIII alone and in combination with varying concentrations of FXIII on end thrombin potential (ETP). The data show that FXIII does not affect thrombin generation.
). Normal clot stability was achieved at very low concentrations of FVIII in the presence of supraphysiologic levels of FXIII (10 μg per milliliter equals a 50% increase in plasma levels, which should be achievable through intravenous infusion of 25 IU per kilogram of body weight) (Figure 1A).Calibrated automated thrombin generation (at 1 pM of tissue factor) was measured after the addition of recombinant FVIII, with and without plasma-derived FXIII (pdFXIII). The speed and quantity of thrombin generation was not altered by the addition of pdFXIII (Mann–Whitney test, P>0.1 for all comparisons) (Figure 1B and 1C).
We have shown that clot stability in patients with hemophilia A can be normalized with the addition of pdFXIII, even at very low levels of FVIII. Data suggest that pdFXIII may correct the imbalance between fibrin formation and FXIII activation in the blood of persons with hemophilia.2 The Km of thrombin-dependent FXIII activation is higher3 than the plasma concentration of FXIII. Hence, the rate of FXIII activation by thrombin should increase if the plasma concentration of FXIII is increased.
These observations suggest that FXIII therapy may be useful as an adjunct in factor-sparing and cost-effective regimens. Because FXIII has a half-life of 9 days,4 dosing would be infrequent, improving convenience and limiting expense. Since FXIII fully corrects plasma clot stability at low concentrations of FVIII, it could be useful in the treatment of bleeding events or in supporting hemostasis during surgery in patients with nonsevere hemophilia. Finally, adjunct FXIII may prove helpful when used in combination with new long-acting FVIII concentrates as a bridging therapy, when FVIII levels are low between doses.
4 ReferencesCatherine J. Rea, M.B., B.Chir.
King's College London, London, United KingdomJonathan H. Foley, Ph.D.
University of Vermont, Burlington, VTBenny Sørensen, M.D., Ph.D.
St. Thomas' Hospital, London, United KingdomDisclosure forms provided by the authors are available with the full text of this letter at NEJM.org.
1
Blomback B Carlsson K Fatah K Hessel B Procyk R
CrossRef | Web of Science | Medline2
Brummel-Ziedins KE Branda RF Butenas S Mann KG
CrossRef | Web of Science | Medline3
Naski MC Lorand L Shafer JA
CrossRef | Web of Science | Medline4
Visich JE Zuckerman LA Butine MD
Web of Science | Medline
- Citing Articles (7)
Citing Articles
1
Mariann Tang, Per Wierup, Catherine J. Rea, Jørgen Ingerslev, Vibeke E. Hjortdal, Benny Sørensen. . (2017) Temporal changes in clot lysis and clot stability following tranexamic acid in cardiac surgery. Blood Coagulation & Fibrinolysis 28:4, 295-302.
CrossRef2
J. Parcq, K. U. Petersen, A. Borel-Derlon, P. Gautier, M. Ebel, D. Vivien, Y. Repessé. . (2017) F376A/M388A-solulin, a new promising antifibrinolytic for severe haemophilia A. Haemophilia 23:2, 319-325.
CrossRef3
H. T. T. Tran, B. Sørensen, C. J. Rea, S. Bjørnsen, T. Ueland, A. H. Pripp, G. E. Tjønnfjord, P. A. Holme. . (2014) Tranexamic acid as adjunct therapy to bypassing agents in haemophilia A patients with inhibitors. Haemophilia 20:10.1111/hae.2014.20.issue-3, 369-375.
CrossRef4
Catherine J. Rea, Jonathan H. Foley, David H. Bevan, Benny Sørensen. . (2014) An in-vitro assessment of tranexamic acid as an adjunct to rFVIII or rFVIIa treatment in haemophilia A. Annals of Hematology 93, 683-692.
CrossRef5
C. J. Rea, J. H. Foley, O. Okaisabor, B. Sørensen. . (2014) FXIII: mechanisms of action in the treatment of hemophilia A. Journal of Thrombosis and Haemostasis 12, 159-168.
CrossRef6
Christopher Ng, Christopher C. Silliman, Gabrielle Pearl, Whitney Smith, Marilyn Manco-Johnson, Michael Wang. . (2013) Treatment of refractory hemorrhage with factor XIII in a patient with hemophilia A with inhibitor. Pediatric Blood & Cancer 60, E23-E25.
CrossRef7
M. S. Jensen, O. H. Larsen, K. Christiansen, C. Fenger-Eriksen, J. Ingerslev, B. Sørensen. . (2013) Platelet activation and aggregation: the importance of thrombin activity-A laboratory model. Haemophilia 19:10.1111/hae.2013.19.issue-3, 403-408.
CrossRef
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