Patient-centered approach to managing factor XIII deficiency

Abstract

Factor XIII (FXIII) is a thrombin-activated protransglutaminase that plays a key role in blood clot formation. Congenital FXIII A-subunit deficiency represents a rare bleeding disorder that affects one in 2–3 million individuals worldwide and is treated with recombinant FXIII (rFXIII). However, due to the rarity of the disease, clinicians are often left to weigh individual variation in FXIII activity and/or symptoms to optimally guide dosing. Cases often become further complicated when patients experience refractory bleeding, which can be difficult to treat. This report describes an approach to rFXIII dosing in two patients who required deviation from standard protocols to maintain therapeutic FXIII troughs. We highlight limitations in our understanding of FXIII deficiency management, while also providing an example of the application of pharmacokinetic data to individualise therapy for improved outcomes. Finally, the case reminds us of the importance of patient-centered, cost-conscious care and multidisplinary teamwork in complex cases.

Background

Factor XIII is a thrombin-activated protransglutaminase consisting of two A and B subunits that plays a role in clot formation and stability.¹ Homozygous congenital deficiency of FXIII, which results from insufficient A or B subunits, represents a rare bleeding disorder that is estimated to affect one in 2–3 million individuals worldwide.^{1 2} The majority of those affected (~95%) are known to have A-subunit deficiency, which is characterised by spontaneous and provoked bleeding; patients may also have recurrent pregnancy losses and impaired wound healing.^3–5 The most typical early manifestation of severe disease is umbilical cord bleeding in infants, though spontaneous intracranial bleeding—a more life-threatening complication—occurs in approximately 30% of those untreated.^{2 6} Fortunately, prophylactic replacement therapy with FXIII has been demonstrated to be safe and effective.2 5 6 6–8

Several factor XIII replacement products are available for the treatment and prophylaxis of bleeding. These include a recombinant factor XIII A subunit (rFXIII; ‘Tretten’) and a factor XIII purified from human plasma (‘Fibrogammin’ and ‘Fibrogammin-P’ in Europe, South America, and Asia; ‘Corifact’ in the USA).^{1 9 10} Factor XIII replacement is facilitated by its long half-life (11 to 14 days), allowing infusion as infrequently as once per month.¹¹ FXIII replacement is generally well tolerated with the disadvantages being limited availability and high cost.^{6 7 12}

Unfortunately, further complicating the management of FXIII deficiency is the fact that there can be individual variation in bleeding tendencies at various levels of FXIII activity. While recent studies have suggested that a FXIII activity of 15% is the level below which the risk of major bleeding increases,¹⁰ others have shown that patients with FXIII levels between 5% and 30% can present in any number of ways, ranging from minor, post‐traumatic bleeding to significant, spontaneous bleeding.¹³ With that in mind, it is not always clear that FXIII activity in plasma is correlated with clinical outcomes in patients.

With this in mind, the complexity and rarity of FXIII deficiency make it a challenging diagnosis. In practice, clinicians are often left to weigh individual variation in FXIII activity and/or symptoms to optimally guide treatment. Cases often become further complicated when patients experience refractory bleeding, which can be difficult to manage. As such, the hope is that this report adds to the available literature in describing a safe and effective approach to the management of patients with FXIII deficiency. Furthermore, we highlight some of the unique patient-centered considerations that go into rare disease management and illustrate the necessity of close collaboration between multidisciplinary teams in the diagnosis and treatment of these patients.

Case presentation

A 7-year-old child with severe FXIII deficiency was brought to a tertiary care hospital after his family had noticed an increase in the frequency of bleeding and bruising episodes over the preceding week. The patient had last received an infusion of rFXIII, on time and as scheduled, 3 weeks prior to presentation. The new increase in bruising was a significant change, as the patient’s family noted that his symptoms had been controlled on replacement FXIII since his diagnosis shortly after birth. Review of systems was otherwise unremarkable. Additionally, the family denied recent growth spurts, missed infusions, or trauma that would have contributed to the symptoms. Of note, the patient’s fraternal twin brother—also with severe FXIII deficiency and on the same treatment schedule—had not experienced a change in bruising or bleeding during this same interval.

As background, both patients had been diagnosed with FXIII deficiency as infants, after presenting with umbilical stump bleeding shortly after birth. Since that time, the patients had received monthly infusions of replacement FXIII without incident. Initial treatment had been with Corifact, and the patients had switched to Tretten (recombinant FXIII) following its Food and Drug Administration (FDA) approval. Their Corifact dosing records were not available to us; however, with Tretten, they had been started at the recommended dose of 35 iu/kg once monthly and doses had been adjusted for weight without issue up to this presentation.

In light of our index patient’s bleeding and bruising episodes, both he and his twin underwent workup that demonstrated FXIII troughs that fell below the detectable level of the quantitative assay (<15%). Of note, they had never previously had troughs <15%. The aetiology of this change in rFXIII metabolism was not clear. One possibility, that the patients had developed a transient inhibitor to FXIII was considered, though was felt less likely.¹⁴ Ultimately, a multidiscipinary haematology board consisting of paediatric haematologists, geneticists and pharmacologists proposed that the patients’ presentation was most similar to the non-linear pharmacokinetic changes observed in other factor deficiencies (eg, haemophilia), in which patients can metabolise replacement products at different rates through their lifespan.^15–17 We came to conclude that a change in our index patient’s metabolism was leading to low troughs, which in turn, was responsible for his easy bruising.

Given this new clinical insight and the paucity of data to guide this unusual case, we turned to the family to inform our next steps. Our decision-making was further complicated by both cost and practical considerations. To that point in their sons’ treatment, the family had purchased a single vial of Tretten once monthly, which was split between their boys to achieve monthly dosing of ~35 iu/kg. Unfortunately, uptitrating the symptomatic twin’s dose would nessistate the purchase of a second vial though much of this would have been wasted since Tretten vials are single-use entities. As such, in an effort to provide patient-centered, cost-consicous care, we chose to uptitrate both boys’ dose to 56 iU/kg (prophylactically, in the asymptomatic twin) in an utilitarian effort to maximise the time interval between future treatments (ie, reduce cost). Notably, the risk of supratherapeutic peak FXIII levels was deemed minimal by our multidisciplinary board, as no published literature to date has reported coagulopathies associated with FXIII infusion.^{9 18} Furthermore, the association between FXIII levels/function and thrombosis risk is complex and the mechanisms by which FXIII contributes to thrombosis in vivo remain unclear.^{19 20}

Ultimately, the patients were asked to return to clinic weekly over the subsequent 4 weeks with good clinical response. The family reported improvement in bruising episodes following the infusion, and pharmacokinetic analyses further verified our suspicion that the patients were rapid metabolisers of rFXIII: the measured half-life of rFXIII in the patients was roughly 7 days versus the 11–14 day estimate in the literature (see figure 1).¹¹ Given the risk of spontaneous haemorrhage with low factor XIII levels and the patients’ active lifestyles, a collective decision was made with the family to continue dosing rFXIII at 56 iu/kg.

Figure 1.

Assessment of Factor XIII (FXIII) activity following uptitration to a dose of 56 iu/kg demonstrated a half-life of roughly 7 days for both our patients versus the 11–14 day estimate in the literature.

Outcome and follow-up

Our patients have now received rFXIII infusions at 56 iu/kg every 3 weeks for 2 years. They have tolerated this regimen well and deny any interval bruising episodes or thromboembolic events.

Discussion

Congenital FXIII deficiency is a challenging and rare diagnosis with a paucity of clinical real-world data to guide therapy. This case highlights limitations in our understanding of treatment, while also providing an example of the application of pharmacokinetic data to individualise therapy for improved patient outcomes. It also reminds us of the importance of patient-centered, cost-conscious care and multidisplinary teamwork in cases of complex disease management.

The idea of individualising patient care in FXIII deficiency warrants further reflection. Literature has previously suggested that effective haemostasis can be achieved with FXIII levels as low as 2%–5%.¹⁰ While this may be true in certain cases, our index patient did not seem to fit this population, highlighting the patient-to-patient variability that must be taken into account. Our results are also important when considering treatment over a patient’s lifespan. It is well known that pharmacokinetics of factor metabolism in haemophilia, for example, are non-linear over time; as such, there is growing interest in using pharmacokinetic-based dosing regimens to optimise the use of clotting factor concentrates in haemophilia.^{15–17 21} Our findings suggest that this concept—of individualising therapy for factor replacement—should be applied to patients with FXIII deficiency as well. This requires further study, especially during times of physiologic change such as puberty or menopause, and even raises a question of whether pharmacokinetic-guided gradual dose reduction might be considered as patients age.

It is also notable that only one of our twins manifested with bleeding despite both showcasing similar FXIII pharmacokinetics. As noted above, evidence does suggest that patients with FXIII activity levels between 5% and 20% have variable bleeding rates.¹³ Our results would seem to further substantiate these data and speak even more convincingly to the importance of individualising therapy for factor replacement. Moreover, these findings remind us that future studies of pharmacokinetics/pharmacodynamics need to take into consideration other potential modifiers of disease severity.

It is worthwhile, too, to note that our case supports the growing evidence that the risk of supratherapeutic peak FXIII levels is minimal. As noted earlier, no literature to date has reported coagulopathies associated with FXIII infusion.^{9 18} Epidemiological studies of FXIII levels suggest that they are an important determinant of thrombus composition and stability, but have yet to show a clear correlation between high FXIII activity and thrombosis risk.^{19 20} The absence of thromboembolic events in our patients further supports this hypothesis, though longer term follow-up and a larger sample size are needed.

Finally, we must emphasise the importance of considering the non-clinical aspects of disease management (ie, cost) that ultimately form the basis of real-world care. In our report, the patient’s family was essential in identifying a practical, financial compromise that ensured that the family could afford necessary treatment. As in this report, the multidisciplinary efforts of haematologists, pharmacists, and social workers is critical in identifying workable solutions in complex cases.

In conclusion, we present a rare case of FXIII deficiency. We emphasise the importance of tailored, patient-centered treatment approaches for rare disease. We also highlight the importance of patient engagement and the role of a multidisciplinary team in the effort to provide holistic care.

Learning points.

• Factor XIII (FXIII) replacement is the standard of care in FXIII deficiency, but management in complex cases can be complicated by the paucity of available data for treating this rare disease.

• FXIII dosing can be individualised using pharmacokinetic data to safely and effectively achieve therapeutic troughs.

• Interdisciplinary conversations between haematologists, geneticists, pharmacists and social workers are critical in providing holistic care for patients.

Ethics statements

Patient consent for publication

Parental/guardian consent obtained.