and14 Manchester Royal Infirmary, Manchester, United Kingdom Key Points• In women presenting with an initial diagnosis of TTP during pregnancy, cTTP was more common than acquired TTP.• Active monitoring and management during pregnancy results in positive pregnancy outcomes.Pregnancy can precipitate thrombotic thrombocytopenic purpura (TTP). We present a prospective study of TTP cases from the United Kingdom Thrombotic Thrombocytopenic Purpura (UK TTP) Registry with clinical and laboratory data from the largest cohort of pregnancy-associated TTP and describe management through pregnancy, averting fetal loss and maternal complications. Thirty-five women presented with a first TTP episode during pregnancy: 23/47 with their first congenital TTP (cTTP) episode and 12/47 with acute acquired TTP in pregnancy. TTP presented primarily in the third trimester/ postpartum, but fetal loss was highest in the second trimester. Fetal loss occurred in 16/38 pregnancies before cTTP was diagnosed, but in none of the 15 subsequent managed pregnancies. Seventeen of 23 congenital cases had a missense mutation, C3178T, within exon 24 (R1060W). There were 8 novel mutations. In acquired TTP presentations, fetal loss occurred in 5/18 pregnancies and 2 terminations because of disease. We also present data on 12 women with a history of nonpregnancy-associated TTP: 18 subsequent pregnancies have been successfully managed, guided by ADAMTS13 levels. cTTP presents more frequently than acquired TTP during pregnancy and must be differentiated by ADAMTS13 analysis. Careful diagnosis, monitoring, and treatment in congenital and acquired TTP have assisted in excellent pregnancy outcomes. (Blood. 2014;124(2):211-219)

Deep vein thrombosis and pulmonary embolism, collectively defined as venous thromboembolism (VTE), are the third leading cause of cardiovascular death in the United States. Common genetic variants conferring increased varying degrees of VTE risk have been identified by genome-wide association studies (GWAS). Rare mutations in the anticoagulant genes PROC, PROS1 and SERPINC1 result in perinatal lethal thrombosis in homozygotes and markedly increased VTE risk in heterozygotes. However, currently described VTE variants account for an insufficient portion of risk to be routinely utilized for clinical decision making. To identify new rare VTE risk variants, we performed a whole exome study of 393 individuals with unprovoked VTE and 6114 controls. This study identified four genes harboring an excess number of rare damaging variants in patients with VTE; PROS1, STAB2, PROC and SERPINC1. At STAB2, 7.8% of VTE cases and 2.4% of controls had a qualifying rare variant. In cell culture, VTE associated variants of STAB2 had a reduced surface expression compared to reference STAB2. Common variants in STAB2 have been previously associated with plasma von Willebrand factor and coagulation factor VIII levels in GWAS, suggesting that haploinsufficiency of stabilin-2 may increase VTE risk through elevated levels of these procoagulants. In an independent cohort, we found higher von Willebrand factor levels and equivalent propeptide levels in individuals with rare STAB2 variants compared to controls. Taken together, this study demonstrates the utility of gene-based collapsing analyses to identify loci harboring an excess of rare variants with functional connections to a complex thrombotic disease.

Background and objectives Acute renal impairment is observed in 11%-23% of patients with congenital thrombotic thrombocytopenic purpura (TTP) and deficiency of a disintegrin and metalloprotease with thrombospondin motifs 13 (ADAMTS13, a metalloprotease that cleaves von Willebrand factor [VWF] multimers), a substantial percentage of whom develop CKD during follow-up.Design, setting, participants, & measurements Here we investigated whether, in 18 patients with congenital recruited from 1996 to 2013 who fulfilled inclusion criteria, acute renal involvement occurred during bouts segregated with lower secretion and activity levels of ADAMTS13 mutants. We performed expression studies and a sensitive recombinant VWF (rVWF) A1-A2-A3 cleavage test (detection limit, 0.78% of normal ADAMTS13 activity).Results A higher risk of acute renal impairment during bouts was observed in patients with childhood (,18 years) onset (odds ratio [OR], 24.6 [95% confidence interval (CI), 1.11 to 542.44]) or a relapsing ($1 episode per year) disease (OR, 54.6 [95% CI, 2.25 to 1326.28]) than in patients with adulthood onset or long-lasting remission, respectively. Whatever the age at onset, patients with acute renal impairment had mutations different from those in patients without renal involvement. Moreover, mutations in patients with acute renal impairment compared with those in patients without renal involvement caused lower in vitro rADAMTS13 secretion (1.33% versus 12.5%; P,0.001) and residual activity (0.11% versus 3.47%; P=0.003). rADAMTS13 secretion #3.75% and residual activity #0.4% best discriminated patients with renal impairment (receiveroperating characteristic curve sensitivity, 100% and 100%; specificity, 100% and 83.3%, respectively; logistic regression OR, 325 [95% CI, 6 to 18339] and 91.7 [95% CI, 3.2 to 2623.5], respectively). All mutations found in patients with childhood onset or relapsing disease were associated with acute renal impairment during bouts, confirming the link between acute renal impairment and early onset or a relapsing course. ADAMTS13 activity levels in vivo, measured in patients' serum by rVWF A1-A2-A3 cleavage test, correlated with in vitro rADAMTS13 mutant activity (r=0.95; P,0.001).Conclusions In congenital TTP, renal impairment and relapsing disease might be predicted by measurements of in vitro rADAMTS13 secretion and activity levels and in vivo serum ADAMTS13 activity.

Congenital thrombotic thrombocytopenic purpura (TTP) is an inherited disease caused by mutations in the ADAMTS 13 gene and has been reported to have diverse ages of presentation, ranging from the newborn period to adulthood. Herein, we present three cases of congenital TTP who were symptomatic during childhood (neonatal period, 7 and 10 years) and were each initially given different diagnoses. Congenital TTP was later diagnosed by molecular analysis and responsiveness to fresh frozen plasma. Three novel mutations in a homozygous state were identified in these patients: c.1308G>C, c.428T>C (p.Ile143Thr) and c.1709A>G (p.Tyr570Cys).

Proteasome degradation of these ADAMTS13 mutants contributed to their reduced secretion.

No abstract

No abstract