Clinical pharmacology of caplacizumab for the treatment of patients with acquired thrombotic thrombocytopenic purpura

Introduction: Caplacizumab is a humanized anti-von Willebrand Factor (vWF) Nanobody® for the treatment of acquired Thrombotic Thrombocytopenic Purpura (aTTP). Caplacizumab targets the A1-domain of vWF, inhibiting the interaction between vWF and platelets. Clinical studies conducted in aTTP patients confirmed the rapid and sustained complete suppression of the vWF activity using an initial intravenous dose of 10 mg, and a maintenance subcutaneous 10 mg daily dosing regimen, with corresponding favorable efficacy and safety profiles.

Areas covered: The pharmacokinetics of caplacizumab are non-linear, characterized by a target-mediated disposition and the exposure is dependent upon drug and target concentration over time. The pharmacokinetics of caplacizumab are predictable when considering the turn-over of the circulating vWF and its modulation by the drug over time. Renal and hepatic impairment are not expected to influence the exposure to the drug, and no direct or indirect drug–drug pharmacokinetic interactions are anticipated based on the mechanism of action and the specificity of the pharmacodynamic effect of caplacizumab.

Expert opinion: Caplacizumab prevents the interaction between vWF and platelets, offering a direct and rapid therapeutic intervention to stop microthrombosis. The combination of caplacizumab with plasma exchange and immunosuppression represents an important, potentially life-saving advance in the treatment of aTTP patients.     

Immunohistochemical localization of vascular endothelial cell factor viii/von Willebrand factor antigen in human normal and disordered gastric tissues

Vascular endothelial cell factor VIII/von Willebrand factor antigen (FVIII/vWF Ag) of normal and disordered gastric tissues was studied with staphyloceocus protein A-gold (PAG) labelling followed by photochemical silver reaction. FVIII/vWF Ag was localized clearly in the tissue fixed with various common fixatives and embedded in paraffin without enzyme treatment. The most satisfactory staining and the least nonspecific background were observed in the tissues fixed with Zamboni’s and Bouin’s solutions. The staining reaction could be enhanced, if the sections were preteateed with trypsin and subtilisin. Under the electron microscope, the gold particles were found over the Weibel-Palade bodies of vascular endothelial cells in the tissues fixed either in Zamboni’s solution or in Zamboni’s solution-osmium tetroxide, and embedded either with Lowicryl K₄M or With Epon 812. It has been proved to be a better technique in investigation of FVIII/vWF Ag in vascular endothelial cells.     

血管紧张素转化酶抑制剂对风湿性心脏病换瓣术后患者血浆中s-ICAM-1、s-VCAM-1和vWF含量的影响

目的观察血管紧张素转化酶抑制剂（ACEI）：雅施达和卡托普利对风心病换瓣术后患者血浆中可溶性黏附分子含量及心功能的影响。方法风湿性心脏病患者90人，术前心功能（NYHA分级）Ⅲ～Ⅳ级，换瓣术后分为雅施达组（30人）、卡托普利组（30人）和对照组（30人），分别给予雅施达、卡托普利和安慰剂治疗。分别于术后4周、8周抽血测定血浆可溶性细胞间黏附分子-1（s—ICAM-1）、可溶性血管细胞间黏附分子-1（s—VCAM-1）和血管性血友病因子（vWF）含量并同时作心功能测定。结果给予雅施达和卡托普利治疗的风心病患者血浆中s—ICAM-1、s—VCAM-1和vWF浓度都低于对照组（P〈0．05），术后4周心功能恢复也好于对照组（P〈0．05），雅施达组和卡托普利组间差异无显著性（P〉0．05）。结论血管紧张素转化酶抑制剂能降低风心病术后患者血浆中可溶性黏附分子水平，尽早改善内皮功能和心肌功能，加强术后心脏功能的恢复，而与血管紧张素转化酶抑制剂（ACEI）的种类无明显相关。     

HMGB1通过TLR2-Myd88途径调控糖尿病中vWF水平

目的探究高迁移率族蛋白(1 HMGB1)-TLR2-MyD88通路在调节糖尿病中血管性血友病因子(vWF)水平的作用。方法使用四氧嘧啶建立糖尿病小鼠模型,使用TLR2抑制剂和激动剂以及HMGB1抑制剂观察糖尿病小鼠中HMGB1-TLR2-MyD88通路中蛋白水平的变化以及小鼠骨巨噬细胞和血浆中vWF含量。结果糖尿病小鼠中骨巨噬细胞vWF含量比正常小鼠高(P0.05),使用TLR2激动剂后正常小鼠中TLR2、MyD88和vWF水平升高(P0.05),使用TLR2沉默RNA刺激糖尿病小鼠,可降调TLR2、MyD88和vWF水平(P0.05)。糖尿病小鼠组中HMGB1水平高于正常小鼠组(P0.05),且使用HMGB1抑制剂后TLR2/MyD88通路以及vWF水平下调(P0.05)。结论本研究表明糖尿病小鼠中表达升高的HMGB1可作为TLR2的一种内源性配体激活TLR2-MyD88通路调节血浆中vWF水平。     

慢性肝炎患者血浆vWF及其前肽与纤溶系统测定的临床意义

目的:探讨肝炎患者血浆vWFpp,vWF,tPA,PAI1及DDimer含量及临床意义.方法:利用ELISA法对肝炎组及对照组血浆vWFpp,vWF,tPA,PAI1及DDimer含量进行测定.结果:肝炎组血浆vWFpp(1.54±1.83)mg/L与对照组(0.43±0.09)mg/L有显著差异,P<0.01;vWF(60.30±99.81)mg/L与对照组(11.27±5.34)mg/L有显著差异(P<0.01);tPA(27.87±14.05)μg/L与对照组(16.70±7.13)μg/L有显著差异(P<0.01);PAI1(43.22±13.53)μg/L与对照组(63.37±6.63)μg/L有显著差异(P<0.01);DDimer(1.02±1.36)mg/L含量与对照组(0.60±0.67)mg/L有显著差异(P<0.01).vWFpp含量与vWF,DDime间具有显著的相关性(P<0.01);tPA含量与PAI1含量间亦具有显著的相关性(P<0.05).其他测定项间无显著的相关性.结论:慢性肝炎患者的血液vWFpp,vWF,D二聚体、tPA及PAI1水平能通过不同途径反映肝病时机体的凝血与纤溶系统的状态,且对于病情的判断和预后具有重要意义.     

肝癌自发性破裂与血管病变

目的 探讨肝癌自发民生破裂的发病机理。方法 选用肝癌破裂及非破裂的患者标本各３９例，采用免疫组化法检测其与血管病变有关的因素包括：第八因子相关抗原；弹性硬蛋白，弹性蛋白酶，ＩＶ型型胶原蛋白和胶原蛋白酶。结果 与非破裂组和相比，肝癌破裂患者中的血管内皮ｖＷＦ因子表达量明显下降（ＶＷＦ因子邓阳性的血管面积，１５８μｍ＾２ｖｓ３６３μｍ＾２，Ｐ〈０．００１）。血管壁中弹性蛋白酶分布异常，弹性硬蛋白增生过     

高血压病患者血浆vWF及D—D水平的变化

目的 探讨凝血因子激活及血管内皮细胞损伤与高现病程和缺血性脑卒中发生发展的关系及其临床意义。方法 用酶联免疫双抗体夹心法分别测定２００例高血压病患（其中包括１８４人次脑卒中患）的血浆Ｄ－二聚体（Ｄ－ｄｉｍｅｒ，Ｄ－Ｄ）和凝血因子Ⅷ相关抗原（ｖｏｎ Ｗｉｌｌｅｂｒａｎｄ Ｆａｃｔｏｒｍ，ｖＷＦ）水平，并用相同的方法测定７０例对照上述指标。结果 高血压病３期血浆ｖＷＦ及Ｄ－Ｄ水平显高于高血压２     

手术创伤对血小板粘附功能的影响

目的探讨手术创伤的大小及时间长短对血小板粘附功能的影响.方法择期胆囊切除术全麻病人30例,随机分为LC组及OC组.两组病人均于全麻后分别采集静脉血10ml,并于手术开始后1h、2h各采血10ml,分别制备贫血小板血浆和富血小板血浆,测定GPⅠ/Ⅰx、vWF、PAdT.结果GPⅠb/Ⅰx、vWF、PAdT麻醉后手术前均无显著性差异.手术中PAdTLC组明显低于OC组(P＜0.05).GPⅠb/ⅠxOC组明显高于LC组(P＜0.01),且随时间延长,OC组亦显著高于LC组(P＜0.01).vWF以LC组减少显著(P＜0.05),两组均在手术开始后2h降低明显.结论手术中GPⅠb/Ⅰx、vWF、PAdT的升高与降低均与创伤大小有关.     

2型糖尿病血管病变与内皮功能关系的研究

目的:观察2型糖尿病(DM)无(A组)与有(B、C组)血管病变者的血管内皮功能。方法:121例2型DM患者被随机分为A、B、C3组,A组不伴有血管病变,42例;B组伴有微血管病变,39例;C组伴大血管病变,40例。另设健康对照组,40例。测定各组的血浆血栓调节蛋白(thrombomodulin,TM)、内皮素-1(ET-1)、血管性假血友病因子(vWF)的含量,并与正常对照组比较。结果:TM在A、B、C组均高于对照组(P<0.05),B、C组又高于A组,差异有显著意义(P<0.05)。ET-1、vWF水平在B、C组高于对照组及A组,差异有显著意义(P<0.05)。结论:DM在血管并发症出现前已存在血管内皮功能的损伤,随着血管病变的发生内皮功能损伤更加明显。     

温阳活血中药复方对冠心病(心)阳虚血瘀证大鼠vWF浓度的影响

目的:研究温阳活血中药复方对冠心痛(心)阳虚血瘀证大鼠vWF浓度的影响.方法:建立冠心病(心)阳虚血瘀证大鼠模型,观察温阳活血中药复方对冠心病(心)阳虚血瘀证大鼠vWF浓度的影响.结果:温阳活血中药复方治疗组与模型组比较,能够显著降低vWF的浓度.结论:温阳活血中药复方能够降低vWF的浓度,抑制释放反应和花生四烯酸代谢(AA代谢),保护内皮细胞,抑制血小板活化.