Experiences in a Family With the Upshaw-Schulman Syndrome Over a 44-Year Period

Abstract

A family with a novel c.717_del frameshift and a c.3655C > T missense mutation of a disintegrin and metalloproteinase with thrombospondin type I motif, member 13 protein (ADAMTS13) is described. Family members have been under observation for 44 years. Two double heterozygotes have severe early-onset Upshaw-Schulman syndrome and require prophylactic plasma infusions. Analysis reveals that 2 weekly plasma infusions are not sufficient in preventing laboratory evidence of a thrombotic thrombocytopenic purpura (TTP) attack. Both the double heterozygotes also have a heterozygous factor V Leiden G1291A mutation. One underwent splenectomy, which did not reduce the frequency of TTP episodes but resulted in a recurrent pulmonary embolism and has necessitated lifelong anticoagulant therapy. The other has mild chronic renal failure and has had episodes of atrial fibrillation and cerebral infarction. Of the 3 heterozygotes in the family, 1 has had episodes of mild thrombocytopenia.

TTP: From empiricism for an enigmatic disease to targeted molecular therapies

“…In line with these statements, a remaining enigmatic aspect of cTTP pathophysiology is the absence of systematic correlation between genotype and phenotype, as illustrated by some families where certain members are severely affected and others with the same allelic mutations on ADAMTS13 gene reach an advanced age with no attacks. Such observations support the existence of triggers but also modifiers in cTTP 75 . The total volume of platelets in circulation of a normal adult is typically only 10–20 ml, making it easy to develop pronounced thrombocytopenia through VWF–platelet aggregates 76 .…”

Current prophylactic plasma infusion protocols do not adequately prevent long‐term cumulative organ damage in the Japanese congenital thrombotic thrombocytopenic purpura cohort

“…Unfortunately, to date, the available sample size is too small to detect statistical differences between the two groups (Supplemental Table SI). On the other hand, a study by Bennet et al 32 . described different disease severities among siblings who had the same pair of ADAMTS13 gene mutations.…”

What's new in the diagnosis and pathophysiology of thrombotic thrombocytopenic purpura

“…20 A male with congenital TTP had a splenectomy at age 18 years, and during the following 18 months had several pulmonary emboli, resulting in chronic oral anticoagulant therapy. 21 Whether these episodes of venous thromboembolism can be attributed directly to the pathophysiology of TTP is uncertain, but the incidence is high enough to consider routine thromboprophylaxis when the platelet count exceeds a minimum threshold such as 50 000 platelets/μL.…”