Conclusion from 50 years of reports on prekallikrein or high-molecular-weight kininogen deficiency

Introduction [if supportFields]><span style='mso-no-proof:yes'><span style='mso-element:field-end'></span></span><![endif]Deficiencies of prekallikrein (PK) and high-molecular-weight kininogen (HK) were discovered in the 1960s and 70s.1,2 Due to their apparent involvement in intrinsic coagulation, scientific interest was focused on hemostasis and possible bleeding during surgeries, as well as a general increase in coagulation activity. Later, knock-out studies in animals suggested protection against pathological clot formation.3,4 Meanwhile, it is very likely that PK and HK do not severely alter hemostasis, as their deficiencies do not cause bleeding diatheses and probably play only a minor role, if any, in thrombotic processes. Aside from coagulation, PK and HK are involved in pathological immunological processes as confirmed in animal models and in individual diseases (e.g. Alzheimer‘s disease, angioedema, diabetes, asthma).5

Method Systematic evaluation of the literature on PK and HK deficiency and the addition of novel cases, to derive prevalence estimates and clinical conclusions.

Results A total of 111 cases of PK deficiency and 48 cases of HK deficiency were identified and comparatively evaluated.6,7 The first ever conducted prevalence estimates revealed an overall frequency of HK deficiency of ~1/8 mio. and of PK deficiency of ~1/150 000, with a high accumulation among Africans (~1/7000).6,7,8 The clinical data evaluation confirmed previous assumptions but had to be limited to a simple description due to evident data gaps and publication bias. For example, the two most informative clinical records covered bleeding and thromboembolic events (missing in 13-19%), but event descriptions were often vague or lacked an assessment of risk factors or family history (missing in 34-72%). Further 44-58% contained no detailed information on clinical pictures except for bleeding/thrombosis, and in 6-9%, even basic details like age or sex were absent [1] [2] [3] [4] [5] [6] [7] [8].

Conclusion Even current reports on cases of PK/HK deficiency almost exclusively adress parameters and medical histories directly related to hemostasis, despite PK’s and HK’s many other functions. The impact of rare defects can be revealed by case reports, but their potential to assess the pathophysiology of PK/HK deficiency is limited. This arises from the constraints of brevity and novelty required for publication, causing data gaps and bias, as well as from our evolving understanding of PK/HK. Therefore, encouraged by our prevalence estimates, we started to establish an ISTH-sponsored international registry on PK and HK deficiency to facilitate consistent and comprehensive reporting with prospective follow-up, which is currently lacking. In addition, future case reports should diversify and detail their clinical reporting to improve data quality.

Publikationsverlauf

Artikel online veröffentlicht:
20. Februar 2023

• References

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