Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin... Show moreImmune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) deficiency, recurring in 30-50% of patients. The common human leukocyte antigen (HLA) variant rs6903608 was found to be associated with prevalent iTTP, but whether this variant is associated with disease relapse is unknown. To estimate the impact of rs6903608 on iTTP onset and relapse, we performed a case-control and cohort study in 161 Italian patients with a first iTTP episode between 2002 and 2018, and in 456 Italian controls. Variation in rs6903608 was strongly associated with iTTP onset (homozygotes odds ratio (OR) 4.68 (95% confidence interval (CI) 2.67 to 8.23); heterozygotes OR 1.64 (95%CI 0.95 to 2.83)), which occurred over three years earlier for each extra risk allele (beta -3.34, 95%CI -6.69 to 0.02). Of 153 survivors (median follow-up 4.9 years (95%CI 3.7 to 6.1)), 44 (29%) relapsed. The risk allele homozygotes had a 46% (95%CI 36 to 57%) absolute risk of relapse by year 6, which was significantly higher than both heterozygotes (22% (95%CI 16 to 29%)) and reference allele homozygotes (30% (95%CI 23 to 39%)). In conclusion, HLA variant rs6903608 is a risk factor for both iTTP onset and relapse. This newly identified biomarker may help with recognizing patients at high risk of relapse, who would benefit from close monitoring or intensified immunosuppressive therapy. Show less
Tati, R.; Kristoffersson, A.C.; Hedstrom, M.M.; Morgelin, M.; Wieslander, J.; Kooten, C. van; Karpman, D. 2017
Von Willebrand factor (VWF) plays an important role in both primary and secondary hemostasis as a molecular glue between platelets and subendothelial structures, and as a carrier of FVIII.... Show moreVon Willebrand factor (VWF) plays an important role in both primary and secondary hemostasis as a molecular glue between platelets and subendothelial structures, and as a carrier of FVIII. Mutations in VWF may cause von Willebrand disease (VWD), which is the most common bleeding disorder. It is characterized by symptoms ranging from very mild to severe bleeding. Mutations may influence the level of VWF (quantitative defect; type 1 or type 3) or may affect the function of VWF. Especially important for the generation of functional VWF is the formation of disulfide linked bonds. Firstly, intrachain linking is essential for the monomer structure. Secondly, interchain linking is necessary for both dimerization and multimerization of VWF. All 169 cysteine residues in the mature VWF subunit (8.2%) participate in these intra- or interchain disulfide bonds. The interaction between proVWF dimers ultimately yields high-molecular weight VWF that is active in primary hemostasis in the bloodstream.The main aims of the studies reported in this thesis were to examine how loss of cysteines located in different domains of VWF results in quantitative and qualitative VWF defects; how these mutations interfere with dimerization and multimerization; and how they influence intracellular routing, secretion and clearance of VWF. Show less
