Kallikrein directly interacts with and activates Factor IX, resulting in thrombin generation and fibrin formation independent of Factor XI.
Kallikrein directly interacts with and activates Factor IX, resulting in thrombin generation and fibrin formation independent of Factor XI.
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DOI：
10.1073/pnas.2014810118
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发表时间：
2021-01-19
影响因子：
11.1
通讯作者：
Philippou H
中科院分区：
文献类型：
--
作者：
Kearney KJ;Butler J;Posada OM;Wilson C;Heal S;Ali M;Hardy L;Ahnström J;Gailani D;Foster R;Hethershaw E;Longstaff C;Philippou H
预钾likrein （PK）是一种通过因子(F)XIIa转化为钾likrein （PKa）的酶原。PK和FXII相互激活；由此产生的FXIIa通过FXI裂解成FXIa激活凝血系统，FXIa随后激活FIX。本文描述了FIX(a)和PK(a)之间一种新型的高亲和力结合相互作用，并报道了PKa可以剂量和时间依赖性地激活FIX产生FIXa，从而导致凝血酶的产生和不依赖于FXIa的凝块形成。FIX活化动力学的表征表明，PKa是一个比以前认为的更重要的FIX活化剂。这项工作强调了对凝血级联的一个新的修正，其中PKa可以直接激活FIX。钾likrein （PKa）由其前体钾likrein （PK）激活产生，在凝血的接触激活阶段起作用，并在钾likrein-kinin系统中起作用，产生缓激肽。一般认为PKa对凝血级联的贡献取决于其对FXII的作用。最近，在人类血浆中，由于PKa对FIX的活性而产生凝血酶，以及在FXI缺陷小鼠中形成fixa -抗凝血酶复合物的小鼠研究，对这一教条提出了挑战。在这项研究中，我们利用表面等离子体共振证明了PK(a)和FIX(a)之间的高亲和力结合相互作用，并表明这些相互作用可能在生理条件下发生。此外，通过十二烷基硫酸钠-聚丙烯酰胺凝胶电泳分析和显色分析，我们直接证明了PKa在纯化体系中对FIX的剂量和时间依赖性裂解作用。通过使用正常的汇集血浆和一系列凝血因子缺陷血浆，我们发现PKa对FIX的作用不仅导致凝血酶的产生，而且在缺乏FXII或FXI的情况下促进纤维蛋白的形成。FXIa和PKa诱导的FIX激活的动力学比较表明，PKa可能是FIX的重要生理激活剂。我们的数据表明，凝血级联需要重新定义，以表明PKa可以直接激活FIX。驱动PKa底物特异性的环境仍有待确定。
Prekallikrein (PK) is a zymogen that is converted to kallikrein (PKa) by factor (F)XIIa. PK and FXII reciprocally activate each other; the resulting FXIIa initiates activation of the coagulation system via the cleavage of FXI to FXIa, which then activates FIX. This manuscript describes a novel high-affinity binding interaction between FIX(a) and PK(a) and reports that PKa can dose- and time-dependently activate FIX to generate FIXa, resulting in thrombin generation and clot formation independent of FXIa. Characterization of the kinetics of FIX activation reveal that PKa is a more significant activator of FIX than previously considered. This work highlights a new amendment to the coagulation cascade where PKa can directly activate FIX. Kallikrein (PKa), generated by activation of its precursor prekallikrein (PK), plays a role in the contact activation phase of coagulation and functions in the kallikrein-kinin system to generate bradykinin. The general dogma has been that the contribution of PKa to the coagulation cascade is dependent on its action on FXII. Recently this dogma has been challenged by studies in human plasma showing thrombin generation due to PKa activity on FIX and also by murine studies showing formation of FIXa-antithrombin complexes in FXI deficient mice. In this study, we demonstrate high-affinity binding interactions between PK(a) and FIX(a) using surface plasmon resonance and show that these interactions are likely to occur under physiological conditions. Furthermore, we directly demonstrate dose- and time-dependent cleavage of FIX by PKa in a purified system by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis and chromogenic assays. By using normal pooled plasma and a range of coagulation factor-deficient plasmas, we show that this action of PKa on FIX not only results in thrombin generation, but also promotes fibrin formation in the absence of FXII or FXI. Comparison of the kinetics of either FXIa- or PKa-induced activation of FIX suggest that PKa could be a significant physiological activator of FIX. Our data indicate that the coagulation cascade needs to be redefined to indicate that PKa can directly activate FIX. The circumstances that drive PKa substrate specificity remain to be determined.
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影响因子：
6.7
作者：
Bird, J. Eileen;Smith, Patricia L.;Seiffert, Dietmar
通讯作者：
Seiffert, Dietmar
影响因子：
2.9
作者：
CHUNG, DW;FUJIKAWA, K;DAVIE, EW
通讯作者：
DAVIE, EW
因子IX因子在血液凝结中的不依赖性作用的证据。
DOI：
10.1111/jth.12435
发表时间：
2013-12
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
--
作者：
Matafonov A;Cheng Q;Geng Y;Verhamme IM;Umunakwe O;Tucker EI;Sun MF;Serebrov V;Gruber A;Gailani D
通讯作者：
Gailani D
影响因子：
56.9
作者：
DAVIE, EW;RATNOFF, OD
通讯作者：
RATNOFF, OD
影响因子：
20.3
作者：
ABILDGAARD, CF;HARRISON, J
通讯作者：
HARRISON, J