Low factor V level ameliorates bleeding diathesis in patients with combined deficiency of factor V and factor VIII
Low factor V level ameliorates bleeding diathesis in patients with combined deficiency of factor V and factor VIII
复制标题
低因子 V 水平可改善因子 V 和因子 VIII 联合缺乏的患者的出血素质
DOI：
10.1182/blood.2018886069
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发表时间：
2019-11-14
期刊：
影响因子：
20.3
通讯作者：
Ding, Qiulan
中科院分区：
文献类型：
--
作者：
Shao, Yanyan;Wu, Wenman;Ding, Qiulan
联合因子V（FV）和FVIII缺乏症（F5 F8 D）是一种罕见的常染色体隐性出血性疾病，由凝集素甘露糖结合-1（LMAN 1）和多种凝血因子缺乏症-2（MCFD 2）突变引起。在6例F5 F8 D患者中发现了6个致病性纯合突变（5个在LMAN 1中，1个在MCFD 2中）。与正常血浆相比，用F5 F8 D血浆中的组织因子（1 pM）触发的凝血酶生成试验矛盾地表现出增强的凝血酶生成。F5 F8 D患者的游离组织因子途径抑制物（fTFPI）显著低于健康对照组（P <0.01）。使F5 F8 D血浆中的组织因子途径抑制剂α（TFPI α）正常化大大延迟并减少凝血酶产生。通过向F5 F8 D血浆中加入血浆FV来增加FV浓度仅引起凝血酶生成的逐渐减少，这表明低水平的TFPI α和FV通过降低抗凝作用而共同促成凝血酶生成的升高。相反，F5 F8 D富血小板血浆（PRP）中的凝血酶生成量明显低于正常对照（P < .05）;然而，通过使FVII正常化或输注1-脱氨基-8-D-精氨酸加压素（DDAVP）后，这一现象得到了完全纠正，这表明F5 F8 D患者的低凝状态与低FVII水平有关。此外，F5 F8 D PRP中的血浆和血小板FV足以支持正常凝血酶生成，低TFPI α可能对凝血酶生成无影响。DDAVP输注诱导5例F5 F8 D患者完全缓解，其余患者部分缓解。根据我们的研究结果，我们认为DDAVP可能被认为是FVIII浓缩物的潜在替代品，对于有轻微出血挑战的F5 F8 D患者，新鲜冷冻血浆（FFP）输注可能不是必要的。
Combined factor V (FV) and FVIII deficiency (F5F8D) is a rare autosomal-recessive bleeding disorder caused by mutations in lectin mannose binding-1 (LMAN1) and multiple coagulation factor deficiency-2 (MCFD2). Six causative homozygous mutations (5 in LMAN1 and 1 in MCFD2) were identified in 6 patients with F5F8D. A thrombin-generation assay, triggered with tissue factor (1 pM) in F5F8D plasma, paradoxically exhibited enhanced thrombin generation compared with normal plasma. Significantly lower free tissue factor pathway inhibitor (fTFPI) was found in F5F8D patients compared with healthy controls (P < .01). Normalizing tissue factor pathway inhibitor alpha (TFPI alpha) in F5F8D plasma greatly delayed and reduced thrombin generation. Increasing FV concentrations by adding plasma FV to F5F8D plasma only caused a gradual decrease in thrombin generation, suggesting that low levels of TFPI alpha and FV cocontributed to the elevated thrombin generation by reducing anticoagulant effects. On the contrary, thrombin generation in F5F8D platelet-rich plasma (PRP) was significantly lower than in normal controls (P < .05); however, it was fully corrected by normalizing FVIII or after 1-deamino-8-D-arginine vasopressin (DDAVP) infusion, indicating that the hypocoagulable state of F5F8D patients is associated with low FVIII levels. In addition, plasma and platelet FV in F5F8D PRP were sufficient to support normal thrombin generation, and low TFPI alpha may have no effect on thrombin generation. DDAVP infusion induced a complete response in 5 F5F8D patients and a partial response in the remaining patient. Based on our findings, we suggest that DDAVP may be considered a potential substitute for FVIII concentrates, and fresh-frozen plasma (FFP) infusion may not be necessary for F5F8D patients with minor bleeding challenges.