TTP: a disorder for all physicians Free

In this issue of Blood, Deshpande et al¹ describe the measurement of plasma ADAMTS13 using rapid assays of ADAMTS13 activity. The absence or severe deficiency of ADAMTS13 is the diagnostic feature of thrombotic thrombocytopenic purpura (TTP). Results can be available in 30 minutes, compared with our current experience of 2 to 3 days. The availability of a rapid assay will provide simplicity for diagnosing TTP. Simplicity will inevitably lead to earlier recognition and may also lead to much more recognition of patients with TTP.

The critical importance of the publication of Deshpande et al is that TTP can now be diagnosed by 1 simple test within an hour. It will revolutionize our clinical practice. There will be prompt recognition and treatment of TTP. The simplicity of the rapid assays may lead to use by medical specialties who see patients with TTP but currently do not recognize them.

Documenting absence or severe deficiency of ADAMTS13 promptly establishes the diagnosis of TTP; treatment can begin immediately. Initial treatment assumes that the patient has the more common acquired, autoimmune TTP (immune TTP [iTTP]) rather than hereditary TTP (congenital TTP [cTTP]). For iTTP, the current appropriate treatment is caplacizumab and rituximab, together with therapeutic plasma exchange and corticosteroids. Caplacizumab binds to the A1 domain of von Willebrand factor (VWF), promptly blocking platelet binding to VWF and preventing thrombosis. Recovery, documented by increasing platelet counts, begins within hours of beginning caplacizumab. Rituximab blocks the production of anti-ADAMTS13 antibodies. Caplacizumab and rituximab may be sufficient. In the future, plasma exchange and corticosteroids may be avoided.

The diagnosis of iTTP is confirmed in several days if anti-ADAMTS13 antibodies are documented. The absence of anti-ADAMTS13 antibodies suggests the diagnosis of cTTP but does not exclude the diagnosis of iTTP. With plasma transfusion, which is always required for patients with TTP, ADAMTS13 is provided and cTTP will recover within a few days. Confirmation of the diagnosis of cTTP requires the documentation of biallelic ADAMTS13 mutations.

These statements describe how the rapid ADAMTS13 activity assays can improve our management of TTP. Also, the rapid ADAMTS13 activity assays can do much more. The simplicity and rapid results of ADAMTS13 activity will attract clinicians beyond our narrow group of hematologists. These rapid ADAMTS13 activity assays are appropriate for many clinical situations (see table). For example, measurement of ADAMTS13 activity could be essential to help a neonatologist manage a newborn infant with severe hyperbilirubinemia, anemia, and thrombocytopenia, which suggests cTTP. Measurement of ADAMTS13 activity could diagnose TTP in a child with recurrent assumed immune thrombocytopenic purpura and moderate thrombocytopenia. Measurement of ADAMTS13 activity could be important for patients with leukemia and cancer who have unexplained anemia and thrombocytopenia. Measurement of ADAMTS13 activity could help an obstetrician care for a woman who appears to have severe preeclampsia at 25 weeks’ gestation, sooner than preeclampsia occurs. The symptoms of preeclampsia and TTP are similar. We hematologists need to help spread the use of the rapid ADAMTS13 activity assays to all of our colleagues.

My statements imply that TTP may be much more common than we now assume. This is certainly true for cTTP. We have assumed that the prevalence of cTTP is 1 patient/10⁶ people.² Now we understand that cTTP may be much more frequent. The global prevalence of cTTP has recently been estimated to be 23/10⁶ people, based on the frequency of the biallelic occurrence of 140 documented pathogenic ADAMTS13 mutations. Including the frequency of all 758 ADAMTS13 mutations that are predicted to be pathogenic, the prevalence of cTTP would be 40/10⁶ people.³ Therefore, we should assume that many people with cTTP are not diagnosed.

The first time of great risk for patients with cTTP is the first minutes of their life, immediately after delivery. Our previous review of cTTP described 204 patients; 83 (42%) were newborn infants with severe jaundice, anemia, and thrombocytopenia at birth.⁴ This is caused by turbulent circulation, which occurs at birth. Turbulence is caused by the reversal of blood flow to provide blood for the lungs. Turbulent circulation causes VWF to unfold, allowing platelet adhesion and causing vascular occlusion. Among all 83 newborn infants, only 4 (5%) were diagnosed as having cTTP. The other infants with cTTP survived because they were assumed to have hemolytic disease of the newborn (a mismatch between the mother's and baby's blood types) and were treated effectively with exchange transfusion. Neonatologists, who manage these infants, need to become familiar with cTTP and the rapid measurement of ADAMTS13. This could establish the diagnosis of cTTP. Appropriate management of the infant would begin the required lifetime ADAMTS13 replacement.

The other time of great risk is during pregnancy. My impression is that women with cTTP never have an uncomplicated pregnancy,⁵ although I would not have seen pregnant women whose cTTP had not been diagnosed. Blood flows through the placenta at a high velocity.⁶ This can cause unfolding of VWF, platelet adhesion, and risk for vascular occlusion. Obstetricians need to become familiar with cTTP and the rapid measurement of ADAMTS13.

The bottom line of my commentary is that all physicians who care for infants, children, and adults should become familiar with the measurement of plasma ADAMTS13 using rapid assays of ADAMTS13 activity. As hematologists, it is our responsibility to tell other physicians about the rapid assays of ADAMTS13 activity. It is so simple. Many measurements will be normal, but recognition of a patient with absent or severe deficiency of ADAMTS13 could save a life. For patients with cTTP, it could guarantee a long, healthy life.

Conflict-of-interest disclosure: The author declares no competing financial interests.