Characterization and treatment of congenital thrombotic thrombocytopenic purpura
Characterization and treatment of congenital thrombotic thrombocytopenic purpura
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DOI：
10.1182/blood-2018-11-884700
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发表时间：
2019-04-11
期刊：
影响因子：
20.3
通讯作者：
Scully, Marie
中科院分区：
文献类型：
--
作者：
Alwan, Ferras;Vendramin, Chiara;Scully, Marie
先天性血栓性血小板减少性紫癜(CTTP)是一种极其罕见的血栓微血管病，由血栓反应蛋白1型成员13(ADAMTS13)去整合素和金属蛋白酶的遗传性缺陷引起。关于基因-表型相关性的数据有限；对于治疗还没有达成共识。我们回顾了过去15年在英国诊断的最大的cTTP病例队列。经基因分析确诊为cTTP患者73例。在审查时，93%的人还活着。36%有纯合子突变；有复合杂合突变。出现两个表现高峰：儿童期(中位诊断年龄，3.5岁)和成年期，通常与怀孕有关(中位诊断年龄，31岁)。基因突变因发病年龄不同而不同，起搏前突变更有可能与儿童发病有关(P=.0011)。69%的成人分娩与怀孕有关。治疗采用新鲜冰冻血浆(FFP)和中纯度凝血因子VIII。88%的血细胞计数正常，但有头痛、嗜睡或腹痛的患者报告说，通过预防性治疗症状得到了缓解。目前最常用的3周一次的FFP方案被证明对70%的患者来说是不够的，需要每周或每两周输液。接受预防性治疗的患者中风发生率显著降低(2%比17%；P=0.04)。从长远来看，存在终末器官损害的风险，75%的晚期诊断为cTTP的患者可以看到这种风险。总之，起搏器前突变与cTTP症状的早期发展有关。预防性ADAMTS13替代降低了缺血性中风等终末器官损害的风险，并解决了非临床疾病患者以前未发现的症状。
Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare thrombomi-croangiopathy caused by an inherited deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). There are limited data on genotype-phenotype correlation; there is no consensus on treatment. We reviewed the largest cohort of cTTP cases, diagnosed in the United Kingdom, over the past 15 years. Seventy-three cases of cTTP were diagnosed, confirmed by genetic analysis. Ninety-three percent were alive at the time of review. Thirty-six percent had homozygous mutations; 64% had compound heterozygous mutations. Two presentation peaks were seen: childhood (median diagnosis age, 3.5 years) and adulthood, typically related to pregnancy (median diagnosis age, 31 years). Genetic mutations differed by age of onset with prespacer mutations more likely to be associated with childhood onset (P = .0011). Sixty-nine percent of adult presentations were associated with pregnancy. Fresh-frozen plasma (FFP) and intermediate purity factor VIII concentrate were used as treatment. Eighty-eight percent of patients with normal blood counts, but with headaches, lethargy, or abdominal pain, reported symptom resolution with prophylactic therapy. The most common currently used regimen of 3-weekly FFP proved insufficient for 70% of patients and weekly or fortnightly infusions were required. Stroke incidence was significantly reduced in patients receiving prophylactic therapy (2% vs 17%; P = .04). Long-term, there is a risk of end-organ damage, seen in 75% of patients with late diagnosis of cTTP. In conclusion, prespacer mutations are associated with earlier development of cTTP symptoms. Prophylactic ADAMTS13 replacement decreases the risk of end-organ damage such as ischemic stroke and resolved previously unrecognized symptoms in patients with nonovert disease.