Jan

20

2025

Hereditary TTP: What Hematologists Should Know

By James N. George, MD

Why hTTP?

Although hereditary thrombotic thrombocytopenic purpura (hTTP) is rare, and rarely symptomatic, there are two times when patients with hTTP have great risk: at birth and during pregnancy. These are times when hTTP should be recognized. 1) Nearly half of newborn infants with hTTP have severe hemolysis and thrombocytopenia, but 95% of these infants are misdiagnosed as having hemolytic disease of the fetus and newborn (HDFN) caused by incompatible fetal-maternal red cell antigens.1 Both hTTP and HDFN respond to treatment with whole blood exchange transfusion. 2) Women with hTTP may always have an exacerbation during their pregnancies; I am not aware of an uncomplicated pregnancy in a woman with hTTP. Preeclampsia is always the assumed diagnosis.

Hematologists should discuss the occurrence of hTTP with neonatologists and obstetricians.

What is my experience with hTTP?

In 1995, I began the Oklahoma TTP Registry, an inception cohort of all consecutive patients in Oklahoma for whom plasma exchange was requested for suspected TTP.2 In 2001, I began to work with Bernhard Lämmle to identify patients in the Registry who had severe deficiency of ADAMTS13.3 I didn’t distinguish acquired, autoimmune and hereditary TTP.

In my 55 years of clinical practice, I have diagnosed hTTP in only 2 families. My first experience was with two sisters, in 1972 and 1974; there was no effective treatment, both were pregnant, both died.45 My second experience was in 2012. I didn’t recognize TTP in an 18-year-old asymptomatic woman admitted with severe thrombocytopenia and microangiopathic hemolytic anemia. I attributed this to her previously diagnosed hereditary elliptocytosis. Three days later her ADAMTS13 activity was reported as undetectable; both of her sisters also had hTTP.2 Later in 2012 I began collaboration with Johanna Kremer, who had established the International hTTP Registry. I enrolled hTTP patients from all of the United States. As I began to learn about hTTP, I recognized how easy it is to not consider the diagnosis of hTTP.

What is the frequency of hTTP?

Until 2024, the frequency of hTTP was determined by the number of diagnosed patients; it was estimated to be 0.5-2.0/106.6 In 2024, the prevalence of hTTP determined by genome sequencing of 807,162 worldwide subjects was reported.7 Among 6321 ADAMTS13 variants, 758 were defined as pathogenic; 140 of the pathogenic variants had been previously reported. Considering both all 758 variants and only the 140 previously reported variants, the estimated prevalences of hTTP were 40 and 23/106. Even these much greater frequencies may be underestimates, since fetuses and newborn infants with hTTP may have died without inclusion with these subjects.

What causes acute episodes of hTTP?

hTTP is caused by the absence or severe deficiency of ADAMTS13, a plasma enzyme required for cleavage of von Willebrand factor (VWF). In the absence of ADAMTS13, VWF

circulates as ultra large molecules (UL-VWF). In normal circulation, UL-VWF is not pathogenic because the platelet binding sites are not exposed. Therefore, most patients with hTTP are asymptomatic most of the time. Turbulent circulation causes the UL-VWF to uncoil, exposing platelet binding sites. Platelets bound to UL-VWF can partially obstruct microvascular circulation, causing the characteristic microangiopathic hemolysis and thrombocytopenia of hTTP.

When does turbulent circulation commonly occur?

In patients with hTTP, turbulent circulation causing acute episodes is apparent at two times: newborn infants and women during pregnancy.

1. Newborn infants: The moment an infant is born, major changes of blood circulation occur. With the infant’s first breaths, the lungs begin to expand and require more oxygen. To provide oxygen, blood circulation to the lungs increases as the ductus arteriosus and the foramen ovale begin to close. These rapid changes cause turbulent circulation; UL-VWF uncoils. Severe microangiopathic hemolysis and thrombocytopenia at birth occurs in 41-49% of newborn infants with hTTP.891011

2. Pregnancy: Women with hTTP may always have hemolysis and thrombocytopenia during pregnancy. Turbulent circulation occurs in the rapid blood flow into and out of the placenta. Turbulent circulation also occurs as blood flows through the placenta’s intervillous spaces.12

Do all patients with hTTP have symptoms?

No. Asymptomatic patients have been identified when ADAMTS13 activity is measured on family members and a sibling has been diagnosed with hTTP. Since ADAMTS13 activity is only measured in patients with suspected TTP and their families, there is very little opportunity to discover asymptomatic hTTP.

Different severity of hTTP among siblings frequently occurs. A striking example is two siblings, now 38 and 42 years old, who are enrolled in the International hTTP Registry. Both siblings have severe deficiency of ADAMTS13. The older sister has had 4 major strokes and multiple disabilities. Her brother is healthy with no symptoms. There could be many undiagnosed, asymptomatic people with severe deficiency of ADAMTS13.

How is hTTP treated?

Acute episodes are treated with intravenous infusion of ADAMTS13. The availability of recombinant ADAMTS13 (Adzynma, Takeda Pharmaceuticals) in 2023 is gradually making the previous standard treatment, plasma exchange, obsolete. Patients who have had major complications need prophylaxis forever. When to recommend lifetime prophylaxis in other patients may be uncertain. Patients who have had infrequent, minor symptoms may be followed carefully without prophylaxis; however prophylaxis may significantly improve their energy and well-being. Some healthy asymptomatic patients (as described above) may never need prophylaxis. Of course, management without prophylaxis has obvious risk; the first symptom of hTTP may be a stroke.

What should hematologists do?

Hematologists need to establish collegial contacts with neonatologists and obstetricians. Neonatologists should suspect hTTP and contact a hematologist when severe neonatal hyperbilirubinemia occurs soon after birth. Obstetricians should suspect hTTP and contact a hematologist when hemolysis and thrombocytopenia is severe or occurs before 30 weeks’ gestation or persists after delivery. Neonatologists and obstetricians should also request ADAMTS13 measurements when they contact a hematologist.

We are currently working with neonatology faculty to publish a review paper in a neonatology journal describing hTTP. We will repeat this process with obstetricians.


Dr. James N. George, MD, is Professor of Medicine at the University of Oklahoma Health Sciences Center (OUHSC). He is past President of the American Society of Hematology President (2005), recipient of the American Society of Hematology (ASH) Wallace H. Coulter Award for Lifetime Achievement in Hematology in 2012 and recipient of the 2024 ASH Award for Leadership in Promoting Diversity. Dr. George is a pioneer in the area of thrombotic thrombocytopenia purpura (TTP). His groundbreaking work over several decades has significantly advanced our understanding of this rare but life-threatening condition. Correspondence13