High-molecular-weight kininogen (HK) circulates bound to prekallikrein(PK), which
can bind to negatively charged phospholipids.It is a non-enzymatic cofactor for kallikrein
binding to negativelycharged phospholipids. Kallikrein activates factor XII, which
then activates factor XI, leading to activation of the intrinsic coagulationpathway
Deficiencies in HK and PK can cause isolated activated partialthromboplastin time
(aPTT) prolongation with normal levels of intrinsic coagulation factors (VIII, IX,
XI, and XII). In PK deficiency,pre-incubation of patient plasma with an aPTT reagent
before aPTT assay shortens the aPTT, whereas in HK deficiency, such pre-incubation
does not correct aPTT prolongation . Severalcases of HK deficiency have been reported
in the Japanese population . Herein we report the first Korean case of congenitalHK
deficiency that resulted in a prolonged aPTT without a change in the pre-incubation
aPTT assay. HK deficiency was confirmed by plasma HK levels and identification of
two pathogenicvariants, one of which was novel (c.488delG). This study was approved
by the institutional review board (IRB) of Seoul National University Hospital (IRB
1911-116-1080). Informed consent for performing genetic testing along with additional
coagulationassays was obtained from the patient.
A 37-year-old man visited the CHA Bundang Medical Center, Seongnam, Korea, for lipoma
surgery. He underwent preoperativeassessment, including coagulation assays, during
which aPTT prolongation was found. He had suffered from peptic ulcerbleeding in his
twenties and had no other medical history related to bleeding or thrombosis. The patient's
peripheral blood specimen was sent to the Seoul National University Hospital (SNUH),
Seoul, Korea for further analysis. The results of laboratoryworkup performed in SNUH
are presented in Table 1: Prothrombintime (PT) and aPTT before preincubation were
12.2 and 177.9 s, respectively. Prolonged aPTT was corrected after a mixing study.
Factors VIII, IX, and XII were within normal ranges, whereas factor XI was slightly
decreased (Table 1).
To exclude immunologic causes of aPTT prolongation, lupus anticoagulant, anti-cardiolipin
antibody, anti-β2GPI antibody, and anti-nuclear antibody were tested, which all turned
out to be negative.Under suspicion of PK deficiency, aPTT was measured after preincubation
with an aPTT reagent for 20 minutes. However,aPTT shortening was not observed: the
re-tested aPTT was 169.7 seconds, and after preincubation it was 132 seconds. PK activity
was of borderline deficiency and PK antigen level was within the reference range.
Sanger sequencing of the KLKB1 gene revealed a normal sequence. On the other hand,
HK activitywas below the detection limit, and HK antigen was very low (Table 1).
Sanger sequencing of the KNG1 gene (exons 1–11 and the flanking regions; NM_000893)
revealed compound heterozygous variants c.488delG and c.1165C>T. A novel variant,
c.488delG in exon 4, which resulted in a frameshift mutation (p.Gly163-Alafs*20),
was assessed as a pathogenic variant based on the 2015 American College of Medical
Genetics and Genomics and the Association for Molecular Pathology guidelines: PVS1
(a frameshiftvariant that leads to a truncated protein), PM2 (absent from controls
in the Exome Aggregation Consortium and Genome AggregationDatabase), and PP4 (highly
specific patient phenotype) . A nonsense mutation caused by c.1165C>T generates
a premature stop codon at position 389 (p.Arg389*). The same variant has been reported
in a patient with severe HK deficiency . Thus, our patient was confirmed as having
HK deficiency with compound heterozygous KNG1 variants. We could not performa family
study because the patient was lost to follow up.
In HK deficiency, PK activity and factor XI have been reported to be decreased or
6]. In our case, PK activity was low, which was measured by the clotting method, and
factor XI was reduced. Both PK and factor XI circulate bound to HK, which explains
the decreased levels of PK and factor XI in our patient.
Patients with HK deficiency are mostly asymptomatic, with prolonged aPTT. Despite
their role in triggering the coagulation pathway, deficiency in any contact activation
system components, including HK, does not lead to bleeding . A few cases of HK
deficiency with thrombosis have been reported: left vertebral basilar artery thromboses,
deep vein thrombosis with pulmonary embolism, and splenic infarction [3
8]. However, the associationbetween HK deficiency and thrombosis has not been clarified.Deletion
of murine kininogen gene 1 (mKng1) delayed thrombosisin an arterial injury model .
A recent study using a murinemodel revealed that HK deficiency protects mice from
ischemicneurodegeneration . In our case, the patient did not have any thrombosis-related
medical history. Because of conflictingresults and limited data on the relationship
between HK deficiency and thrombosis, we suggest that in cases of HK deficiencywith
thrombosis, other causes of thrombosis should be thoroughly investigated to clarify
whether the finding is coincidental,and thrombosis formation should be closely followed