Blocking domain 6 of high molecular weight kininogen to understand intrinsic clotting mechanisms.
Blocking domain 6 of high molecular weight kininogen to understand intrinsic clotting mechanisms.
复制标题
DOI：
10.1002/rth2.12815
复制
发表时间：
2022-10
影响因子：
4.6
通讯作者：
Norris EH
中科院分区：
文献类型：
--
作者：
Singh PK;Chen ZL;Horn K;Norris EH
接触系统由因子(F)XII激活和高分子激肽原(HK)与FXI或前激肽释放酶(PK)在带负电的表面组装而启动。这一系统的过度激活会导致多种疾病的血栓形成和炎症。为了开发有效的治疗接触系统疾病的方法，需要对这一途径有详细的了解。我们在正常人血浆和各种因子缺乏的血浆中进行了凝血试验。为了评估HK介导的PK和FXI激活如何促进凝血，我们使用了抗HK抗体来阻断对HK结构域6的访问，该区域是有效激活PK和FXI所需的区域。FXI与HK结合，随后被激活的FXII激活，有助于凝血。我们发现，3E8抗HK抗体可以抑制FXI或PK与HK的结合，从而延缓人血浆中血栓的形成。我们的数据表明，在没有FXI的情况下，PK可以在这一过程中替代FXI。加入激活的FXI(Fxia)或激活的PK(PKA)可阻断3E8的抑制作用。此外，加入FXIa可在很大程度上绕过内源性凝血对HK的要求。与FXIa一样，外源性PKA缩短了HK缺乏血浆的凝血时间，这不是由于FXII的反馈激活所致。这项研究加深了我们对HK介导的凝血的理解，并为HK缺陷个体没有出血提供了解释。3E8特异性地阻止HK介导的FXI激活，因此，它可以在不改变止血的情况下用于预防接触性激活介导的血栓形成。
The contact system is initiated by factor (F) XII activation and the assembly of high molecular weight kininogen (HK) with either FXI or prekallikrein (PK) on a negatively charged surface. Overactivation of this system contributes to thrombosis and inflammation in numerous diseases. To develop effective therapeutics for contact system disorders, a detailed understanding of this pathway is needed. We performed coagulation assays in normal human plasma and various factor‐deficient plasmas. To evaluate how HK‐mediated PK and FXI activation contributes to coagulation, we used an anti‐HK antibody to block access to domain 6 of HK, the region required for efficient activation of PK and FXI. FXI's binding to HK and its subsequent activation by activated FXII contributes to coagulation. We found that the 3E8 anti‐HK antibody can inhibit the binding of FXI or PK to HK, delaying clot formation in human plasma. Our data show that in the absence of FXI, however, PK can substitute for FXI in this process. Addition of activated FXI (FXIa) or activated PK (PKa) abolished the inhibitory effect of 3E8. Moreover, the requirement of HK in intrinsic coagulation can be largely bypassed by adding FXIa. Like FXIa, exogenous PKa shortened the clotting time in HK‐deficient plasma, which was not due to feedback activation of FXII. This study improves our understanding of HK‐mediated coagulation and provides an explanation for the absence of bleeding in HK‐deficient individuals. 3E8 specifically prevented HK‐mediated FXI activation; therefore, it could be used to prevent contact activation‐mediated thrombosis without altering hemostasis.
登录
查看更多内容
影响因子：
16.6
作者：
Göbel K;Pankratz S;Asaridou CM;Herrmann AM;Bittner S;Merker M;Ruck T;Glumm S;Langhauser F;Kraft P;Krug TF;Breuer J;Herold M;Gross CC;Beckmann D;Korb-Pap A;Schuhmann MK;Kuerten S;Mitroulis I;Ruppert C;Nolte MW;Panousis C;Klotz L;Kehrel B;Korn T;Langer HF;Pap T;Nieswandt B;Wiendl H;Chavakis T;Kleinschnitz C;Meuth SG
通讯作者：
Meuth SG
影响因子：
20.3
作者：
Chen, Zu-Lin;Revenko, Alexey S.;Strickland, Sidney
通讯作者：
Strickland, Sidney
影响因子：
56.9
作者：
GAILANI, D;BROZE, GJ
通讯作者：
BROZE, GJ
影响因子：
11.1
作者：
Englert H;Rangaswamy C;Deppermann C;Sperhake JP;Krisp C;Schreier D;Gordon E;Konrath S;Haddad M;Pula G;Mailer RK;Schlüter H;Kluge S;Langer F;Püschel K;Panousis K;Stavrou EX;Maas C;Renné T;Frye M
通讯作者：
Frye M
DOI：
10.1073/pnas.2014810118
发表时间：
2021-01-19
影响因子：
11.1
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
通讯作者：
Philippou H