Keywords bradykinin - prekallikrein - kininogen
A 67-year-old veteran came to our emergency department because of the sudden onset
of tongue swelling and the inability to swallow saliva. His past medical history included
type 2 diabetes mellitus, essential hypertension, and plasma prekallikrein deficiency.
He had no itching or previous history of allergic reaction. He had been previously
diagnosed to have plasma prekallikrein deficiency as his PTT had ranged from 90 to
<120 seconds on different occasions (normal <35 seconds) The plasma kallikrein level
was less 3% by coagulation assays. No immunoreactive prekallikrein was detected in
the plasma by western blot ([Fig. 1 ]). All other coagulation factors had been in the normal range, including factor XII.
He had never had a bleeding diathesis. He started taking lisinopril for hypertension
3 months before the onset of angioedema. His physical examination was unremarkable
except for oropharyngeal angioedema. He received intravenous dexamethasone, ranitidine,
and diphenhydramine, and his symptoms resolved over several hours.
Fig. 1. Mutation in prekallikrein gene. (A ) Immunoblot of plasma. Two microliter of control and patient was electrophoresed
and blotted with an antibody to plasma prekallikrein (clone 13G11 from Invitrogen).
(B ) Sequencing traces of PCR amplified exon 5 depicting the homozygous single nucleotide
(*) insertion in codon 132, leading to frameshift all of subsequent codons. PCR, polymerase
chain reaction.
Deoxyribonucleic acid (DNA) was extracted from peripheral blood leukocytes and all
15 exons of prekallikrein gene (KLKB1) were amplified by polymerase chain reaction (PCR) using genomic DNA as the template
and sequenced. He had a homozygous single nucleotide insertion of thymine in codon
132, in exon 5, that caused amino acid change (Ser to Phe) and frameshift of subsequent
codons resulting in a premature stop at codon 173 ([Fig. 1 ]). To our knowledge, this mutation has never been described before. This exon codes
for the apple 2 domain and a previously described amino acid substitutions (Asn to
Ser in codon 124) were also present.[1 ]
Angiotensin-converting enzyme (ACE) not only catalyzes the conversion of angiotensin
I to II but also degrades plasma bradykinin (which induces vasodilation and increased
vascular permeability) by proteolysis to inactive metabolites[2 ]
[3 ]. Substantial increase in bradykinin levels during acute attacks has been shown in
patients with ACE-induced angioedema.[4 ] Occurrence of angioedema in a patient with complete deficiency of plasma prekallikrein
shows other possible enzymes capable of liberating bradykinin such as factor XIIa,
plasmin, or tissue kallikreins may also play a role in generating bradykinin during
ACE inhibitor therapy ([Fig. 2 ]). Mutation of the angiopoietin-1 gene (ANGPT1 ) can also induce angioedema independent of bradykinin.[5 ] These enzyme or proteins can be possible etiologies for angioedema independent of
plasma kallikrein. In humans, plasma prekallikrein is coded by a single gene KLKB1 , while tissue kallikreins are a family of 15 closely related serine proteases (KLK1-15 ). At least two tissue kallikreins, KLK1 and KLK2 , can generate bradykinin from low molecular weight kininogen.[6 ] Salivary secretion is a rich source of tissue kallikreins. The oropharynx with abundant
saliva is the most common site of angioedema associated with ACE. It is pertinent
to note that bradykinin, generated in the plasma during plasmapheresis or during infections,
is associated with hypotension but not angioedema.[7 ]
[8 ] These clinical observations raise the possibility that bradykinin generated by tissue
kallikrein present in the salivary secretions may have a causal role in oropharyngeal
angioedema in patients receiving ACE inhibitors.
Fig. 2. The kallikrein proteolytic cascade. The preferred substrate for plasma kallikrein
is high molecular weight kininogen while tissue kallikreins metabolize low and high
molecular weight kininogen.
