An isolated result showing aPTT prolongation suggests a deficiency or inhibitor of one or more of the intrinsic pathway clotting factors (prekallikrein, high molecular weight kininogen
, factors XII, XI, IX, and VIII).
Only a few peptides were derived from less abundant proteins such as C4, clusterin (also known as apolipoprotein J), high-molecular-mass kininogen
, and coagulation factor XIII.
Because of the extreme susceptibility of ITIH4 to plasma kallikrein and the partial homology of the amino acid sequence to that of bradykinin released from high-molecular-mass kininogen
by plasma kallikrein, human ITIH4 had been proposed to be a potential precursor of bioactive peptides (1, 2).
hK1 exerts its biological activity mainly through the release of lysyl-bradykinin (kallidin) from low-molecular-weight kininogen
. However, the diverse expression pattern of hK1 has led to the suggestion that the functional role of this enzyme may be specific to different cell types (29, 30).
Human Hageman factor (factor XII) and high molecular weight kininogen
compete for the same binding site on human umbilical vein endothelial cells.
Structurally, FXI is a homodimer; each subunit contains four apple domains (which form a disk structure with binding sites for platelets, HMW kininogen
, and factor IX) and a protease domain (Gailani and Smith, 2009).
KVD900 provided critical high molecular weight kininogen
cleavage protection for at least 10 hours.
(31) The study reported differential expression of 16 proteins, of which low molecular weight kininogen
(LMWK) was up-regulated in all 3 samples, indicating a role of this protein in BCR signaling of CLL cells.
Orally administered KVD900 achieved rapid and dose-dependent plasma exposure over the range of doses tested from 5 mg to 600 mg A single 600 mg dose provided greater than 90% plasma kallikrein inhibition and protection of high molecular weight kininogen
cleavage from dextran sulphate-stimulated cleavage shown by capillary-based immunoassay.
Along with these functions, it also inhibits the formation of bradykinin from kininogen
. A deficiency of C1-INH therefore causes an increase in kallikrein activity, resulting in excessive production of bradykinin.
Bradykinin (BK) is a nine amino acid vasoactive peptide that is produced by the proteolytic action of kallikrein on the precursor kininogen
Alteplase results in a secondary increase in bradykinin due to the cleavage of high molecular weight kininogen
. This overproduction of bradykinin may in part be responsible for tPA induced angioedema.