Dissociation between the level of von Willebrand factor‐cleaving protease activity and disease in a patient with congenital thrombotic thrombocytopenic purpura

Abstract

Decreased von Willebrand factor (VWF)-cleaving protease activity (<5%) has been implicated in patients with congenital thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (Upshaw-Schulman syndrome) and associated with mutations within the ADAMTS13 gene. In this report, we describe longitudinal studies in a patient with congenital TTP who ultimately developed end-stage renal failure and required plasma therapy from infancy. The patient was deficient in plasma high molecular weight (HMW)-VWF multimers during acute disease but had increased amounts of the HMW-VWF multimers during periods of remission. DNA analysis of this patient detected homozygosity for the R692C mutation on exon 17 of the ADAMTS13 gene, previously linked to congenital TTP. The level of VWF-cleaving protease activity in the patient was remarkably low (<5%) throughout her disease, even after she entered complete remission. However, despite no improvement in the level of VWF-cleaving protease activity, this patient had complete resolution of disease following splenectomy and commencing hemodialysis, without need for ongoing plasma therapy. The patient has remained in remission for over 4 years. These observations suggest that there are other factors in conjunction with severe deficiency of VWF protease activity that participate in the platelet-mediated thrombotic complications and other disease manifestations of congenital TTP. In addition, it is possible that splenectomy could be an effective treatment option for some patients with severe, congenital TTP. Am.

ADAMTS13 and microvascular thrombosis

“…These and subsequent studies demonstrate that inhibitory autoantibodies are detectable in most patients with acquired TTP (32). Furthermore, following the first study linking hereditary TTP to mutations of the ADAMTS13 gene (4), other studies have identified more mutations in patients with the disease (33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45). Together these two lines of evidence confirm that ADAMTS13 deficiency plays a pivotal role in causing the VWFplatelet thrombosis of TTP.…”

“…DNA nucleotide sequence analysis has detected at least 9 nonsense, 42 missense, 9 frameshifting insertion or deletion, and 6 splicing mutations (4,(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45). These mutations span the entire length of the protein without apparent hot spots.…”

Thrombotic thrombocytopenic purpura related to severe ADAMTS13 deficiency in children

“…Most patients under plasmatherapy have stopped having TTP relapses. Some cases of treatment failure may have been related to insufficient amounts of plasma infused or too long an interval between infusions [19,22,32,44,77]. No role of alloimmunization anti-ADAMTS13 has ever been demonstrated.…”

Long term follow up of congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome) on hemodialysis for 19 years: a case report

“…The mechanism is assumed to be that splenectomy decreases autoantibody production by removing a large reservoir of B lymphocytes [14], which is a reasonable explanation for patients with acquired TTP and elevated levels of ADAMTS13 inhibitor. However, Snider et al [15] reported a patient with relapsing and refractory congenital TTP who remained in complete clinical remission for 4 years after splenectomy. In our patient, remission of TTP persisted for 10 years after splenectomy, but the effect was limited.…”