Fatal congenital thrombotic thrombocytopenic purpura with apparent ADAMTS13 inhibitor: in vitro inhibition of ADAMTS13 activity by hemoglobin

Abstract

Severe ADAMTS13 deficiency in thrombotic thrombocytopenic purpura (TTP) is either constitutional and caused by ADAMTS13 mutations, or acquired and most often due to ADAMTS13 inhibitory autoantibodies. In strongly hemolytic serum of a pediatric patient, diagnosed with TTP postmortem, ADAMTS13 activity was less than 3%. Both parents had an AD-AMTS13 activity of approximately 50%. Sequencing of the ADAMTS13 gene revealed an intronic 687-2A>G substitution affecting exon 7, homozygous in the propositus and heterozygous in both parents, confirming constitutional AD-AMTS13 deficiency. ADAMTS13 activity of normal plasma was inhibited by incubation with the propositus' serum, suggesting alloantibody formation to ADAMTS13. However, immunoglobulin purified from serum had no ADAMTS13 inhibitory effect, whereas the immunoglobulin-

The D173G mutation in ADAMTS-13 causes a severe form of congenital thrombotic thrombocytopenic purpura

“…Inherited TTP is a rare autosomal recessive disorder due to homozygous or double heterozygous mutations in the ADAMTS-13 gene, causing a severe decrease of ADAMTS-13 level and activity (10)(11)(12)(13)(14)(15)(16). About 100 mutations causing inherited ADAMTS-13 deficiency have been identified so far in regions of the gene encoding different domains (10)(11)(12)(13)(14)(15)(16)(17) with only a few of them characterized by in vitro expression studies (12,15,(18)(19)(20)(21)(22). In this manuscript, we report cases of congenital TTP, due to the homozygous mutation in ADAMTS-13 gene in two young brothers born from two consanguineous parents of Romanian origin.…”

Plasma von Willebrand factor level and its associated parameters: Reference ranges in Nigeria

“…This function if defective may lead to various forms of thrombotic disorders. Conditions which may regulate the cleavage of VWF by ADAMTS-13 include-flow shear stress (Tsai, 1996;Tsai and Lian 1998;Tsai 2003), heparin sulphate, platelet glycoprotein-Ibα (GP Ibα) (Nishio et al, 2004), sodium chloride (De Cristofaro et al, 2005), inflammatory cytokines (Bernardo et al, 2004) and haemoglobin (Studt et al, 2005). The mechanisms underlying the activity of ADAMTS-13 in the various blood groups need further investigations.…”

Cardiac involvement in thrombotic microangiopathies

“…Установлено, что свобод-ный гемоглобин, особенно гем, способны активировать ЭК, ин-дуцируя воспаление и тромбоз, а также подавлять продукцию ими оксида азота (NO), приводя к вазоконстрикции и активации тромбоцитов [39]. Кроме того, недавно в условиях in vitro показа-но, что гемоглобин может ингибировать активность ADAMTS-13 [40], что, по-видимому, также может усиливать процесс микро-тромбообразования.…”