Abstract
Exposure of blood to foreign surfaces induces reciprocal conversion of the plasma proteins factor XII (fXII) and plasma prekallikrein (PPK) to the proteases α-fXIIa and α-kallikrein. This process, called contact activation, has a range of effects on host defence mechanisms, including promoting coagulation. The nature of the triggering mechanism for contact activation is debated. One hypothesis predicts that fXII has protease activity, either intrinsically or upon surface-binding, that initiates contact activation. We tested this by assessing the proteolytic activity of a recombinant fXII variant that cannot be converted to α-fXIIa. Recent findings The proteolytic activity of fXII-T (for 'triple' mutant), a variant with alanine substitutions for arginine at activation cleavage sites (Arg334, Arg344, and Arg353) was tested with known α-fXIIa substrates. FXII-T activates PPK in solution, and the reaction is enhanced by polyphosphate, an inducer of contact activation released from platelets. In the presence of polyphosphate, fXII-T converts fXII to α-fXIIa, and also converts the coagulation protein factor XI to its active form. Summary: The findings support the hypothesis that contact activation is initiated through activity intrinsic to single-chain fXII, and indicate that preexisting α-fXIIa is not required for induction of contact activation.
| Original language | English |
|---|---|
| Pages (from-to) | 411-418 |
| Number of pages | 8 |
| Journal | Current Opinion in Hematology |
| Volume | 24 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 1 Sep 2017 |
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Keywords
- contact activation
- factor XI
- factor XII
- plasma prekallikrein
ASJC Scopus subject areas
- Hematology
Cite this
Single-chain factor XII : A new form of activated factor XII. / Ivanov, Ivan; Matafonov, Anton; Gailani, David.
In: Current Opinion in Hematology, Vol. 24, No. 5, 01.09.2017, p. 411-418.Research output: Contribution to journal › Review article
}
TY - JOUR
T1 - Single-chain factor XII
T2 - A new form of activated factor XII
AU - Ivanov, Ivan
AU - Matafonov, Anton
AU - Gailani, David
PY - 2017/9/1
Y1 - 2017/9/1
N2 - Exposure of blood to foreign surfaces induces reciprocal conversion of the plasma proteins factor XII (fXII) and plasma prekallikrein (PPK) to the proteases α-fXIIa and α-kallikrein. This process, called contact activation, has a range of effects on host defence mechanisms, including promoting coagulation. The nature of the triggering mechanism for contact activation is debated. One hypothesis predicts that fXII has protease activity, either intrinsically or upon surface-binding, that initiates contact activation. We tested this by assessing the proteolytic activity of a recombinant fXII variant that cannot be converted to α-fXIIa. Recent findings The proteolytic activity of fXII-T (for 'triple' mutant), a variant with alanine substitutions for arginine at activation cleavage sites (Arg334, Arg344, and Arg353) was tested with known α-fXIIa substrates. FXII-T activates PPK in solution, and the reaction is enhanced by polyphosphate, an inducer of contact activation released from platelets. In the presence of polyphosphate, fXII-T converts fXII to α-fXIIa, and also converts the coagulation protein factor XI to its active form. Summary: The findings support the hypothesis that contact activation is initiated through activity intrinsic to single-chain fXII, and indicate that preexisting α-fXIIa is not required for induction of contact activation.
AB - Exposure of blood to foreign surfaces induces reciprocal conversion of the plasma proteins factor XII (fXII) and plasma prekallikrein (PPK) to the proteases α-fXIIa and α-kallikrein. This process, called contact activation, has a range of effects on host defence mechanisms, including promoting coagulation. The nature of the triggering mechanism for contact activation is debated. One hypothesis predicts that fXII has protease activity, either intrinsically or upon surface-binding, that initiates contact activation. We tested this by assessing the proteolytic activity of a recombinant fXII variant that cannot be converted to α-fXIIa. Recent findings The proteolytic activity of fXII-T (for 'triple' mutant), a variant with alanine substitutions for arginine at activation cleavage sites (Arg334, Arg344, and Arg353) was tested with known α-fXIIa substrates. FXII-T activates PPK in solution, and the reaction is enhanced by polyphosphate, an inducer of contact activation released from platelets. In the presence of polyphosphate, fXII-T converts fXII to α-fXIIa, and also converts the coagulation protein factor XI to its active form. Summary: The findings support the hypothesis that contact activation is initiated through activity intrinsic to single-chain fXII, and indicate that preexisting α-fXIIa is not required for induction of contact activation.
KW - contact activation
KW - factor XI
KW - factor XII
KW - plasma prekallikrein
UR - http://www.scopus.com/inward/record.url?scp=85020729441&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85020729441&partnerID=8YFLogxK
U2 - 10.1097/MOH.0000000000000363
DO - 10.1097/MOH.0000000000000363
M3 - Review article
AN - SCOPUS:85020729441
VL - 24
SP - 411
EP - 418
JO - Current Opinion in Hematology
JF - Current Opinion in Hematology
SN - 1065-6251
IS - 5
ER -