Clinical Pearls & Morning Reports
Published October 23, 2019
Hereditary thrombotic thrombocytopenic purpura (TTP), also known as Upshaw–Schulman syndrome, is a rare autosomal recessive disorder caused by ADAMTS13 mutations that result in the absence or severe deficiency of the plasma metalloprotease ADAMTS13. ADAMTS13 is required for cleavage of newly synthesized von Willebrand factor multimers. In the absence of ADAMTS13, the ultralarge von Willebrand factor multimers persist, leading to spontaneous platelet adherence and aggregation. Some patients with hereditary TTP may have symptoms that manifest at birth, whereas others remain asymptomatic for decades. Read the Review Article here.
Q: What are some of the clinical scenarios in which a diagnosis of hereditary TTP should be considered?
A: Although patients with hereditary TTP are at increased risk for manifestations of microvascular thrombosis throughout their lives, two periods appear to be associated with extreme risk. These periods are the first days of life and pregnancy. The diagnosis of hereditary TTP should be considered in all neonates who have severe hyperbilirubinemia, especially when thrombocytopenia is present. Patients with hereditary TTP have a high risk of transient ischemic attack (TIA) and stroke, beginning at a young age. Clinicians caring for patients who have a TIA or stroke at a young age, particularly when there is concurrent thrombocytopenia, should consider the diagnosis of TTP. In women presenting with very-early-onset preeclampsia (e.g., at <25 weeks of gestation), hereditary TTP should be considered.
Q: What are some of the known triggers for an acute episode of hereditary TTP?
A: Inflammatory conditions such as infection and trauma and the use of drugs or excessive alcohol intake can increase the risk of thrombosis by causing increased endothelial secretion of von Willebrand factor. However, acute episodes may have no apparent triggering factor, and microvascular thrombosis may be silent.
A: Plasma infusion is usually sufficient to treat acute episodes of TTP, although for severe manifestations (e.g., in pregnancy) therapeutic plasma exchange may be appropriate. For patients who have recurrent symptoms, regular lifetime prophylactic plasma infusions are appropriate, although the decision to begin prophylaxis is difficult, especially in a child. On the basis of the clinical symptoms and the goal to maintain each patient’s normal platelet count, treatment intervals between plasma infusions of 14 to 21 days are possible, but the best ADAMTS13 threshold to prevent long-term end-organ damage is unknown. The development of inhibitory ADAMTS13 alloantibodies in patients receiving plasma therapy has been reported twice. This outcome is different from the outcome with factor VIII replacement in patients with hemophilia A, in whom anti–factor VIII alloantibodies have developed in one third.
A: The availability of recombinant human ADAMTS13 (rhADAMTS13) may revolutionize the management of hereditary TTP. The simplicity of this treatment, which consists of the injection of approximately 5 ml of rhADAMTS13 every 2 to 3 weeks at home, may allow patients to begin lifetime treatment when the diagnosis of hereditary TTP is established. Gene therapy has been reported to be successful in ADAMTS13 knockout mice, although whether it will have a role in the future management of hereditary TTP is currently unknown.