Prekallikrein deficiency due to homozygous KLKB1(+) mutation c.444_445insT (p.Ser151PhefsTer34)

Definite diagnosis of plasma prekallikrein deficiency should not be based exclusively on shortening of the aPTT upon prolonged pre‐incubation

“…Dear Editors, We read with interest the report by Abraham et al 1 on the first Indian patient with plasma prekallikrein (PK) deficiency and are pleased that it further supports our recent findings. 2,3 Nevertheless, we would like to point out some inconsistencies regarding the reported variant, and we disagree with the authors' statement that correction of a prolonged aPTT after prolonged pre-incubation is sufficient to diagnose PK deficiency.…”

“…Further database searches revealed that a similar frequency is observed in other African nations and African descendants, such as African Americans and Caribbean, so the previously assumed rarity of this defect is no longer tenable. 3 Furthermore, we disagree with the recommendation of Abraham et al 1 to rely on the aPTT normalization after a prolonged preincubation period for firmly diagnosing PK deficiency. Despite the fact that complete normalization is indeed specific for PK deficiency, 4 it was only described in about 30 of 48 cases of PK deficiency, whereas only a considerable shortening could be documented in the remaining 18 cases (overview: "aPTT after prolonged pre-incubation" in Barco et al, 2 for details refer to individual papers).…”

“…Alternatively, the detection of biallelic KLKB1 variants is appropriate to establish the diagnosis. Genetics but not the aPTT test confirmed the diagnosis in the case reported by Abraham et al 1 Since only two KLKB1 variants have been repeatedly described in the literature as causes of PK deficiency (c.451dupT, p.Ser151Phefs*34 [rs560588447] in Africans and individuals of African descent, and c.1643G>A, p.Cys548Tyr…”

“…We would like to emphasize that the variant described in the letter of Abraham et al 1 has not only been found in heterozygosity so far. 5 The correct nomenclature of the variant at the DNA level according to the Human Genome Variation Society (HGVS) facilitates the search for previously described cases.…”

“…Abraham et al 1 identified a case with a massively prolonged aPTT but without a bleeding diathesis. After ruling out the usual causes, they hypothesized a deficiency of PK or high-molecularweight kininogen (HK).…”